Is ACTG1 p.Ser145Ala (c.433T>G) pathogenic?

ACTG1 p.Ser145Ala (c.433T>G) is classified Uncertain significance in ACTG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-17). AlphaMissense: ambiguous (0.5096); Absent from gnomAD v4.1; Associated with Baraitser-winter syndrome 2.

What condition is associated with ACTG1 p.Ser145Ala (c.433T>G)?

ACTG1 p.Ser145Ala (c.433T>G) is associated with Baraitser-winter syndrome 2, autosomal dominant nonsyndromic hearing loss 20 (ClinVar).

How common is ACTG1 p.Ser145Ala (c.433T>G) in the general population?

ACTG1 p.Ser145Ala (c.433T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTG1 p.Ser145Ala (c.433T>G)?

AlphaMissense predicts ambiguous (score 0.5096) — an in-silico prediction, not a clinical call.

ACTG1 p.Ser145Ala

c.433T>G · rs2143779284 · VCV1462182

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5096 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Baraitser-winter syndrome 2

Computational evidence

Protein change
AlphaMissense	0.5096	ambiguous
REVEL	0.875	moderately pathogenic-leaning
SaProt	LLR -12.80	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 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.09	constrained · MANE · 164 bp · p 4.4e-16 · regional, not allelic
Overall
CADD	29.7	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

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.Ser145Ala
Coding: c.433T>G
MANE Select: NM_001614
dbSNP: rs2143779284
Type: single nucleotide variant
Location: chr17:81511557 (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

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

Also linked: autosomal dominant nonsyndromic hearing loss 20

Similar variants

ACTG1 p.Ser145Phe Likely pathogenic ★ same residue
ACTG1 p.Ser145Cys 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-ser145ala (accessed [today's date]).

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