Is ACTG1 p.Phe90Ser (c.269T>C) pathogenic?

ACTG1 p.Phe90Ser (c.269T>C) is classified Uncertain significance in ACTG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-24). AlphaMissense: likely pathogenic (0.997); Absent from gnomAD v4.1; Associated with autosomal dominant nonsyndromic hearing loss 20.

What condition is associated with ACTG1 p.Phe90Ser (c.269T>C)?

ACTG1 p.Phe90Ser (c.269T>C) is associated with autosomal dominant nonsyndromic hearing loss 20, Baraitser-winter syndrome 2 (ClinVar).

How common is ACTG1 p.Phe90Ser (c.269T>C) in the general population?

ACTG1 p.Phe90Ser (c.269T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTG1 p.Phe90Ser (c.269T>C)?

AlphaMissense predicts likely pathogenic (score 0.997) — an in-silico prediction, not a clinical call.

ACTG1 p.Phe90Ser

c.269T>C · rs2544391851 · VCV2947949

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nonsyndromic hearing loss 20

Computational evidence

Protein change
AlphaMissense	0.997	likely pathogenic
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -13.65	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 367 bp · p 2.2e-06 · regional, not allelic
Overall
CADD	31.0	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

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.Phe90Ser
Coding: c.269T>C
MANE Select: NM_001614
dbSNP: rs2544391851
Type: single nucleotide variant
Location: chr17:81511997 (GRCh38)
Gene constraint: LOEUF 0.617 · pLI 0.46 (gnomAD)
Structure: AlphaFold pLDDT 95.44 · 11 PDB
Residue 90: a turn

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.Phe90= Likely benign ★ same residue
ACTG1 p.Phe90Leu 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-phe90ser (accessed [today's date]).

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