GENE & BIOLOGY · ALLELES

Move from gene-level certainty to an allele-specific molecular question.

The ASH1L gene–disease relationship is established. The transcript, RNA consequence, protein output, localization, chromatin engagement, and residual function of a specific molecular finding still require allele-aware measurement.

GENE & ALLELE ESSENTIALS

Gene and allele essentials

Start here for the established gene–disease relationship, reference systems, dosage evidence, and the measurements needed to move from a variant label to an allele-specific molecular consequence.

SCIENTIFIC BOTTOM LINE

Established disease mechanism. Measured molecular functions. Major allele-to-person gaps.

ESTABLISHED IN PEOPLE

ASH1L haploinsufficiency causes a neurodevelopmental disorder.

ClinGen classifies the autosomal-dominant gene–disease relationship as Definitive and finds sufficient evidence that loss of one functional copy is disease-causing.

This is gene-level evidence. It does not functionally classify every reported allele.

DIRECTLY MEASURED

ASH1L is a regulated, multi-domain chromatin protein.

Biochemistry and structural studies support nucleosome-context H3K36 mono- and dimethylation, MRG15-dependent stimulation, and separable DNA-, histone-, and nucleosome-engagement functions.

The measured output depends on construct, partner, substrate, locus, and assay.

NOT YET ESTABLISHED

There is no molecular severity rule, biomarker, or validated treatment target.

Variant class or position does not reliably predict residual function, vulnerable cell type, clinical course, or response to an intervention.

Patient-allele RNA, protein, chromatin, cell-state, and rescue studies remain essential.

THE CAUSAL CHAIN

Every arrow needs its own evidence.

A gene-level diagnosis does not by itself reveal the RNA product, protein consequence, affected chromatin loci, vulnerable cell state, or cause of an individual clinical feature.

01GENE DOSAGE
Is one functional copy insufficient?
Established at gene level
02ALLELE → RNA
Which transcript is used, and does RNA decay, splice differently, or escape?
Usually unmeasured
03RNA → PROTEIN
How much full-length protein remains, where is it localized, and which interactions persist?
Allele-specific question
04CHROMATIN ACTION
Which loci, marks, partners, and transcriptional programs change in the relevant state?
Context-dependent
05CELL → PERSON
Which cell functions and human outcomes follow, and do correction or rescue normalize them?
Needs evidence linking cell changes to human outcomes

Gene ≠ allelePosition ≠ functionMark ≠ mechanismModel ≠ personAssociation ≠ attribution

GENE IDENTITY & REFERENCE SYSTEMS

Reference identity and dosage

One gene can have multiple valid reference systems, and coordinates are not portable. Clinical interpretation must preserve the transcript, genome build, cDNA notation, protein reference, and isoform. This page uses the MANE Select transcript and protein as its clinical coordinate system, then crosswalks UniProt explicitly.

HGNC-APPROVED IDENTITY

ASH1L

ASH1 like histone lysine methyltransferase

HGNC: 19088
NCBI Gene: 55870
Locus: 1q22
Inheritance: Autosomal dominant

CLINICAL REFERENCE

MANE Select

NM_018489.3 transcript
NP_060959.2 protein
Q9NR48-2 UniProt isoform · 2,964 aa

These identifiers describe the same MANE protein reference used for the clinical scale on this page.

ALTERNATIVE CANONICAL REFERENCE

UniProt Q9NR48-1

NM_001366177.2 transcript
NP_001353106.1 protein · 2,969 aa

This is a different transcript–protein pair, not the UniProt name for NP_060959.2.

EXACT CROSSWALK BREAKPOINT

Q9NR48-1 residues 2,035–2,039 are VFFVS.

Those five residues have no MANE counterpart. Positions 1–2,034 map 1:1; MANE 2,035–2,964 maps to canonical 2,040–2,969. Verify the accession and reference residue before comparing a variant, feature, or construct.

GENE–DISEASE VALIDITYDefinitive

Autosomal-dominant syndromic complex neurodevelopmental disorder.

ClinGen · February 23, 2023

HAPLOINSUFFICIENCYScore 3

Sufficient evidence that loss of one functional copy is disease-causing.

ClinGen · last evaluated December 27, 2017

TRIPLOSENSITIVITYScore 0

No current evidence supporting dosage pathogenicity from an extra copy.

Absence of evidence is not evidence of safety for every duplication architecture.

HGNC ↗NCBI Gene ↗ClinGen gene validity ↗ClinGen dosage ↗UniProt ↗

FROM FINDING TO FUNCTION

From variant class to measured consequence

Variant class generates a hypothesis. It does not finish the mechanism. The correct first question is not “Where is the variant?” but “What RNA and protein products remain?” Functional dosage can be altered by abundance, localization, complex assembly, catalytic control, chromatin engagement, or more than one route.

Scroll horizontally to review every column.

Allele-aware interpretation framework. Every row states a plausible consequence, a required measurement, and an invalid shortcut.
Molecular class	Plausible consequences	What must be measured	Invalid shortcut
Truncating / predicted loss of function	Nonsense-mediated decay, transcript escape, shortened protein, reduced dosage, or an altered product.	Transcript and exon use; allele-specific RNA; decay/escape; full-length and truncated protein; localization.	Do not draw a missing-domain protein unless escape and translation are demonstrated.
Missense / in-frame	Altered folding, stability, localization, partner binding, catalytic control, DNA or nucleosome engagement.	Protein abundance and localization; interaction, nucleosome, catalytic, and rescue assays matched to the affected region.	Position inside a domain does not prove loss of function, gain of function, dominant-negative action, or severity.
Splice	Exon skipping, cryptic splice use, intron retention, frame change, partial in-frame product, or mixed transcripts.	RNA from an informative tissue or validated model, ideally with long-read confirmation and protein follow-up.	A predicted splice effect is not the same as an observed RNA consequence.
CNV / deletion	ASH1L dosage loss with possible contribution from neighboring genes or regulatory elements.	Coordinates, genome build, genes and elements included, inheritance, orthogonal confirmation, and phenotype comparison.	A multigene deletion cannot be interpreted as an isolated ASH1L sequence variant.
Complex / mixed / additional finding	More than one plausible molecular contributor, structural event, mosaic state, or unresolved architecture.	Phase, segregation, copy-number structure, additional findings, tissue distribution where relevant, and whether conclusions change when each possible contributor is considered separately.	Do not force a complex result into a single-allele severity ladder.