Is ACTG1 p.Arg335Cys (c.1003C>T) pathogenic?

ACTG1 p.Arg335Cys (c.1003C>T) is classified Conflicting classifications of pathogenicity in ACTG1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2024-11-06). AlphaMissense: likely pathogenic (0.9934); Very rare (popmax 8.47e-05%, nfe); Associated with ACTG1-related disorder.

What condition is associated with ACTG1 p.Arg335Cys (c.1003C>T)?

ACTG1 p.Arg335Cys (c.1003C>T) is associated with ACTG1-related disorder, autosomal dominant nonsyndromic hearing loss 20 (ClinVar).

How common is ACTG1 p.Arg335Cys (c.1003C>T) in the general population?

ACTG1 p.Arg335Cys (c.1003C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ACTG1 p.Arg335Cys (c.1003C>T)?

AlphaMissense predicts likely pathogenic (score 0.9934) — an in-silico prediction, not a clinical call.

ACTG1 p.Arg335Cys

c.1003C>T · rs1568060200 · VCV561396

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9934 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ACTG1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9934	likely pathogenic
REVEL	0.932	strongly pathogenic-leaning
SaProt	LLR -11.78	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 6.5	GERP 0.44, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 397 bp · p 8e-16 · regional, not allelic
Overall
CADD	31.0	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) · 1/1,179,990 alleles

Overall 6.84e-05% 1/1,461,666 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.Arg335Cys
Coding: c.1003C>T
MANE Select: NM_001614
dbSNP: rs1568060200
Type: single nucleotide variant
Location: chr17:81510815 (GRCh38)
Gene constraint: LOEUF 0.617 · pLI 0.46 (gnomAD)
Structure: AlphaFold pLDDT 95.44 · 11 PDB
Residue 335: an α-helix

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

Disease context

ACTG1-related disorder

Also linked: autosomal dominant nonsyndromic hearing loss 20

Similar variants

ACTG1 p.Arg335His Pathogenic/Likely pathogenic ★★ same residue
ACTG1 p.Arg335Leu Pathogenic ★ same residue
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

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-arg335cys (accessed [today's date]).

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