Is ACTG1 p.Ala231Val (c.692C>T) pathogenic?

ACTG1 p.Ala231Val (c.692C>T) is classified Uncertain significance in ACTG1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-15). AlphaMissense: ambiguous (0.4492); Very rare (popmax 0.0022%, sas); Associated with autosomal dominant nonsyndromic hearing loss 20.

What condition is associated with ACTG1 p.Ala231Val (c.692C>T)?

ACTG1 p.Ala231Val (c.692C>T) is associated with autosomal dominant nonsyndromic hearing loss 20, Baraitser-winter syndrome 2 (ClinVar).

How common is ACTG1 p.Ala231Val (c.692C>T) in the general population?

ACTG1 p.Ala231Val (c.692C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about ACTG1 p.Ala231Val (c.692C>T)?

AlphaMissense predicts ambiguous (score 0.4492) — an in-silico prediction, not a clinical call.

ACTG1 p.Ala231Val

c.692C>T · rs782069591 · VCV2037789

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4492 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

autosomal dominant nonsyndromic hearing loss 20

Computational evidence

Protein change
AlphaMissense	0.4492	ambiguous
REVEL	0.564	indeterminate
SaProt	LLR -13.76	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 265 bp · p 0.016 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,096 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.00217% 35/1,613,690 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0878%	1,139
Remaining individualsnot grpmax-eligible	0.0048%	20,828
South Asiangrpmax	0.0022%	45,548
European (non-Finnish)	0.000339%	295,015

Ashkenazi Jewish 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: ACTG1
Protein: p.Ala231Val
Coding: c.692C>T
MANE Select: NM_001614
dbSNP: rs782069591
Type: single nucleotide variant
Location: chr17:81511298 (GRCh38)
Gene constraint: LOEUF 0.617 · pLI 0.46 (gnomAD)
Structure: AlphaFold pLDDT 95.44 · 11 PDB

Full ACTG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant nonsyndromic hearing loss 20 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Baraitser-winter syndrome 2

Similar variants

ACTG1 p.Ala231= Benign ★★ same residue
ACTG1 p.Ala231Thr Uncertain significance ★ ⚠ same residue
ACTG1 p.Ala135Val Pathogenic/Likely pathogenic ★★ same condition
ACTG1 p.Ala204Gly Likely pathogenic ★★ same condition
ACTG1 p.Arg183Gln Pathogenic/Likely pathogenic ★★ same condition
ACTG1 p.Arg183Trp Pathogenic/Likely pathogenic ★★ same condition
ACTG1 p.Arg206Gln Pathogenic/Likely pathogenic ★★ same condition
ACTG1 p.Arg210Cys Pathogenic ★★ 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/actg1-p-ala231val (accessed [today's date]).

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