Is ACTG1 p.Ala114Val (c.341C>T) pathogenic?

ACTG1 p.Ala114Val (c.341C>T) is classified Uncertain significance in ACTG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-30). AlphaMissense: ambiguous (0.3459); Very rare (popmax 8.47e-05%, nfe); Associated with autosomal dominant nonsyndromic hearing loss 20.

What condition is associated with ACTG1 p.Ala114Val (c.341C>T)?

ACTG1 p.Ala114Val (c.341C>T) is associated with autosomal dominant nonsyndromic hearing loss 20, Baraitser-winter syndrome 2 (ClinVar).

How common is ACTG1 p.Ala114Val (c.341C>T) in the general population?

ACTG1 p.Ala114Val (c.341C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ACTG1 p.Ala114Val (c.341C>T)?

AlphaMissense predicts ambiguous (score 0.3459) — an in-silico prediction, not a clinical call.

ACTG1 p.Ala114Val

c.341C>T · VCV3751327

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3459 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

autosomal dominant nonsyndromic hearing loss 20

Computational evidence

Protein change
AlphaMissense	0.3459	ambiguous
REVEL	0.784	moderately pathogenic-leaning
SaProt	LLR -13.13	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 0.76, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 334 bp · p 0.28 · regional, not allelic
Overall
CADD	26.5	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 8.47e-05% European (non-Finnish) · 1/1,180,020 alleles

Overall 0.000137% 2/1,461,784 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,500
European (non-Finnish)grpmax	8.47e-05%	1,180,020

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: ACTG1
Protein: p.Ala114Val
Coding: c.341C>T
MANE Select: NM_001614
Type: single nucleotide variant
Location: chr17:81511925 (GRCh38)
Gene constraint: LOEUF 0.617 · pLI 0.46 (gnomAD)
Structure: AlphaFold pLDDT 95.44 · 11 PDB
Residue 114: an α-helix

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.Ala114= Likely benign ★ 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
ACTG1 p.Arg254Trp Pathogenic/Likely 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-ala114val (accessed [today's date]).

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