Is TRRAP p.Ala3764Val (c.11291C>T) pathogenic?

TRRAP p.Ala3764Val (c.11291C>T) is classified Uncertain significance in TRRAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.7963); Very rare (popmax 0.000424%, nfe); Associated with hearing loss, autosomal dominant 75.

What condition is associated with TRRAP p.Ala3764Val (c.11291C>T)?

TRRAP p.Ala3764Val (c.11291C>T) is associated with hearing loss, autosomal dominant 75, developmental delay with or without dysmorphic facies and autism (ClinVar).

How common is TRRAP p.Ala3764Val (c.11291C>T) in the general population?

TRRAP p.Ala3764Val (c.11291C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about TRRAP p.Ala3764Val (c.11291C>T)?

AlphaMissense predicts likely pathogenic (score 0.7963) — an in-silico prediction, not a clinical call.

TRRAP p.Ala3764Val

c.11291C>T · rs1212619468 · VCV2582431

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7963 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

hearing loss, autosomal dominant 75

Computational evidence

Protein change
AlphaMissense	0.7963	likely pathogenic
REVEL	0.416	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 3,855 bp · p 4.2e-18 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A3750V vs ClinVar A3764V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,052 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,614,248 alleles · very rare exomes 7/1,461,872 · genomes 0/152,376 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,255
European (non-Finnish)grpmax	0.000424%	236,010

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TRRAP
Protein: p.Ala3764Val
Coding: c.11291C>T
MANE Select: NM_001375524
dbSNP: rs1212619468
Type: single nucleotide variant
Location: chr7:99011489 (GRCh38)
Gene constraint: LOEUF 0.115 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)

Full TRRAP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hearing loss, autosomal dominant 75 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental delay with or without dysmorphic facies and autism

Similar variants

TRRAP p.Ala3764= Likely benign ★ same residue
TRRAP p.Arg1035Gln Pathogenic/Likely pathogenic ★★ same condition
TRRAP p.Glu1104Gly Pathogenic/Likely pathogenic ★★ same condition
TRRAP p.Met3318Val Pathogenic/Likely pathogenic ★★ same condition
TRRAP p.Ala1995Thr Uncertain significance ★★ same condition
TRRAP p.Ala3669Val Uncertain significance ★★ ⚠ same condition
TRRAP p.Ala953Thr Uncertain significance ★★ same condition
TRRAP p.Arg171His Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/trrap-p-ala3764val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown