connected people
Everyone included in the group-level summaries on this site.
VARIANT LANDSCAPE
Reference systems & interpretation
Keep denominators, transcripts, proteins, coordinate systems, consequence, and measured mechanism separate.
WHAT EACH COUNT MEANS
3 counts that look similar answer different questions.
people with a molecular result recorded
Molecular descriptions are recorded for all 65 people, drawing on laboratory results and family-reported information.
people shown on the single-position map
The 34 LoF/truncating and 19 single-missense results that can each be shown at one protein position.
ALL 65 CONNECTED PEOPLE
All molecular categories are shown before the distinct position map.
Bar length represents the share of the 65 connected people. It is not an effect-size or severity scale.
- Reported LoF / truncating35 people35
- Missense19 people19
- CNV / deletion5 people5
- Complex / mixed / in-frame3 people3
- Splice, protein undefined3 people3
REFERENCE SYSTEMS
An amino-acid number is not an allele identity.
Different transcripts and protein isoforms can number the same variant differently. Keep the original transcript, protein accession, genome build, and isoform, and convert coordinates before comparing positions.
MANE clinical reference
NM_018489.3 transcript
NP_060959.2 protein
Q9NR48-2 UniProt isoform
UniProt canonical reference
NM_001366177.2 transcript
NP_001353106.1 protein
Q9NR48-1 UniProt isoform
Q9NR48-1 residues 2,035–2,039 have no MANE counterpart.
The references match through residue 2,034. After the insertion, convert MANE to canonical by adding 5; convert canonical positions 2,040–2,969 to MANE by subtracting 5.
Open the full reference identity →Shared sequence before the insertionMANE 1–2,034 ↔ UniProt 1–2,034
Canonical-only insertionUniProt 2,035–2,039 · VFFVS ↔ no MANE residue
Shared sequence after the insertionMANE 2,035–2,964 ↔ UniProt 2,040–2,969
Do not apply a blanket 5-residue shift. The mapping is 1:1 through 2,034, contains a 5-residue canonical-only gap, and shifts only after that breakpoint. Verify the accession and reference residue before comparing a variant, domain, or construct.
FROM CONSEQUENCE TO MECHANISM
Gene-level certainty does not functionally classify every allele.
ASH1L haploinsufficiency is established at the gene level. Sequence consequence, predicted RNA fate, protein effect, clinical classification, and functional evidence must still be evaluated separately for an individual allele.
Reduced ASH1L dosage can cause disease.
ClinGen supports an autosomal-dominant gene–disease relationship and sufficient haploinsufficiency evidence.
The exact molecular route remains a measurement question.
Predicted NMD, predicted escape, unresolved RNA fate, protein abundance, localization, complex assembly, and functional output are distinct states.
Open the consequence-to-measurement matrix4 molecular contexts · required measurements · invalid shortcuts
What RNA and protein products remain?
Measure: Transcript and exon use; allele-specific RNA; predicted NMD, predicted escape, or unresolved RNA fate; full-length and shorter protein; localization.
Do not infer: A stop, frameshift, or splice consequence does not by itself prove NMD, absence of protein, or allele-specific functional loss.
Which molecular function changes, if any?
Measure: Protein abundance, folding, localization, partner binding, nucleosome engagement, catalytic control, and correction or rescue in a relevant state.
Do not infer: Missense is a sequence consequence—not a mechanism, pathogenicity class, or severity category.
Which transcripts are actually produced?
Measure: RNA from an informative tissue or validated model, ideally with long-read confirmation and protein follow-up.
Do not infer: A predicted splice effect is not the same as an observed RNA consequence.
What is the complete molecular architecture?
Measure: Interval and genome build, genes and elements included, phase, segregation, copy-number structure, additional findings, and tissue distribution where relevant.
Do not infer: A multigene or multi-event result cannot be forced into a single-allele position or severity ladder.