Is ACTG1 p.Thr77Ser (c.230C>G) pathogenic?

ACTG1 p.Thr77Ser (c.230C>G) is classified Uncertain significance in ACTG1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-02-27). AlphaMissense: likely benign (0.3377); Very rare (popmax 0.0011%, sas); Associated with autosomal dominant nonsyndromic hearing loss 20.

What condition is associated with ACTG1 p.Thr77Ser (c.230C>G)?

ACTG1 p.Thr77Ser (c.230C>G) is associated with autosomal dominant nonsyndromic hearing loss 20, Baraitser-winter syndrome 2 (ClinVar).

How common is ACTG1 p.Thr77Ser (c.230C>G) in the general population?

ACTG1 p.Thr77Ser (c.230C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ACTG1 p.Thr77Ser (c.230C>G)?

AlphaMissense predicts likely benign (score 0.3377) — an in-silico prediction, not a clinical call.

ACTG1 p.Thr77Ser

c.230C>G · rs2143783478 · VCV1690354

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3377 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nonsyndromic hearing loss 20

Computational evidence

Protein change
AlphaMissense	0.3377	likely benign
REVEL	0.846	moderately pathogenic-leaning
SaProt	LLR -9.06	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 367 bp · p 2.2e-06 · regional, not allelic
Overall
CADD	27.5	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 0.0011% South Asian · 1/91,084 alleles

Overall 0.000137% 2/1,461,706 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,084
European (non-Finnish)	8.47e-05%	1,180,038

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.Thr77Ser
Coding: c.230C>G
MANE Select: NM_001614
dbSNP: rs2143783478
Type: single nucleotide variant
Location: chr17:81512036 (GRCh38)
Gene constraint: LOEUF 0.617 · pLI 0.46 (gnomAD)
Structure: AlphaFold pLDDT 95.44 · 11 PDB
Residue 77: a β-strand

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.Thr77= Conflicting classifications of pathogenicity ★ same residue
ACTG1 p.Thr77Ala 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-thr77ser (accessed [today's date]).

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