Is ACTG1 p.Arg254Trp (c.760C>T) pathogenic?

ACTG1 p.Arg254Trp (c.760C>T) is classified Pathogenic/Likely pathogenic in ACTG1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2024-09-10). AlphaMissense: likely pathogenic (0.9964); Absent from gnomAD v4.1; Associated with Baraitser-winter syndrome 2.

What condition is associated with ACTG1 p.Arg254Trp (c.760C>T)?

ACTG1 p.Arg254Trp (c.760C>T) is associated with Baraitser-winter syndrome 2, autosomal dominant nonsyndromic hearing loss 20, lissencephaly spectrum disorders (ClinVar).

How common is ACTG1 p.Arg254Trp (c.760C>T) in the general population?

ACTG1 p.Arg254Trp (c.760C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTG1 p.Arg254Trp (c.760C>T)?

AlphaMissense predicts likely pathogenic (score 0.9964) — an in-silico prediction, not a clinical call.

ACTG1 p.Arg254Trp

c.760C>T · rs281875328 · VCV29589

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9964 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Baraitser-winter syndrome 2

Computational evidence

Protein change
AlphaMissense	0.9964	likely pathogenic ✓ concordant with ClinVar
REVEL	0.729	pathogenic-leaning
SaProt	LLR -13.15	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP -0.58, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 265 bp · p 0.016 · regional, not allelic
Overall
CADD	26.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACTG1
Protein: p.Arg254Trp
Coding: c.760C>T
MANE Select: NM_001614
dbSNP: rs281875328
Type: single nucleotide variant
Location: chr17:81511230 (GRCh38)
Gene constraint: LOEUF 0.617 · pLI 0.46 (gnomAD)
Structure: AlphaFold pLDDT 95.44 · 11 PDB
Residue 254: a UniProt-annotated variant site (in brws2); an α-helix

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

Disease context

Baraitser-winter syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant nonsyndromic hearing loss 20 lissencephaly spectrum disorders

Similar variants

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.Arg335His Pathogenic/Likely pathogenic ★★ same condition
ACTG1 p.Asp51Asn 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-arg254trp (accessed [today's date]).

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