Is ACTG1 p.Ser281Cys (c.842C>G) pathogenic?

ACTG1 p.Ser281Cys (c.842C>G) is classified Conflicting classifications of pathogenicity in ACTG1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-04-30). AlphaMissense: ambiguous (0.5558); Very rare (popmax 8.47e-05%, nfe); Associated with hearing loss disorder.

What condition is associated with ACTG1 p.Ser281Cys (c.842C>G)?

ACTG1 p.Ser281Cys (c.842C>G) is associated with hearing loss disorder, autosomal dominant nonsyndromic hearing loss 20 (ClinVar).

How common is ACTG1 p.Ser281Cys (c.842C>G) in the general population?

ACTG1 p.Ser281Cys (c.842C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ACTG1 p.Ser281Cys (c.842C>G)?

AlphaMissense predicts ambiguous (score 0.5558) — an in-silico prediction, not a clinical call.

ACTG1 p.Ser281Cys

c.842C>G · rs2143775658 · VCV1065023

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5558 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hearing loss disorder

Computational evidence

Protein change
AlphaMissense	0.5558	ambiguous
REVEL	0.789	moderately pathogenic-leaning
SaProt	LLR -14.31	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 8.5	GERP -3.8, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 397 bp · p 8e-16 · regional, not allelic
Overall
CADD	29.1	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,046 alleles

Overall 6.84e-05% 1/1,461,724 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.Ser281Cys
Coding: c.842C>G
MANE Select: NM_001614
dbSNP: rs2143775658
Type: single nucleotide variant
Location: chr17:81511069 (GRCh38)
Gene constraint: LOEUF 0.617 · pLI 0.46 (gnomAD)
Structure: AlphaFold pLDDT 95.44 · 11 PDB
Residue 281: an α-helix

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

Disease context

hearing loss disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant nonsyndromic hearing loss 20

Similar variants

ACTG1 p.Ala135Val Pathogenic/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.Arg254Trp Pathogenic/Likely pathogenic ★★ same condition
ACTG1 p.Asp51Asn Pathogenic/Likely pathogenic ★★ same condition
ACTG1 p.Glu241Lys Pathogenic/Likely pathogenic ★★ same condition
ACTG1 p.Lys118Met 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-ser281cys (accessed [today's date]).

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