Is ACTG1 p.Ala230Asp (c.689C>A) pathogenic?

ACTG1 p.Ala230Asp (c.689C>A) is classified Uncertain significance in ACTG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-15). AlphaMissense: likely pathogenic (0.9887); Very rare (popmax 0.00133%, afr); Associated with Baraitser-winter syndrome 2.

What condition is associated with ACTG1 p.Ala230Asp (c.689C>A)?

ACTG1 p.Ala230Asp (c.689C>A) is associated with Baraitser-winter syndrome 2, autosomal dominant nonsyndromic hearing loss 20 (ClinVar).

How common is ACTG1 p.Ala230Asp (c.689C>A) in the general population?

ACTG1 p.Ala230Asp (c.689C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ACTG1 p.Ala230Asp (c.689C>A)?

AlphaMissense predicts likely pathogenic (score 0.9887) — an in-silico prediction, not a clinical call.

ACTG1 p.Ala230Asp

c.689C>A · rs782124831 · VCV2196600

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9887 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Baraitser-winter syndrome 2

Computational evidence

Protein change
AlphaMissense	0.9887	likely pathogenic
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -16.18	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 7.4	GERP -0.4, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 265 bp · p 0.016 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,060 alleles

Overall 6.84e-05% 1/1,461,434 alleles · very rare

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.Ala230Asp
Coding: c.689C>A
MANE Select: NM_001614
dbSNP: rs782124831
Type: single nucleotide variant
Location: chr17:81511301 (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.Ala230= Likely benign ★★ same residue
ACTG1 p.Ala230Thr Uncertain significance ★ ⚠ same residue
ACTG1 p.Ala230Val Likely pathogenic ★ 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

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-ala230asp (accessed [today's date]).

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