Is ACTG1 p.Phe262Leu (c.786C>G) pathogenic?

ACTG1 p.Phe262Leu (c.786C>G) is classified Uncertain significance in ACTG1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-28). AlphaMissense: likely pathogenic (0.9932); Ultra-rare (popmax 0.066%, mid); Associated with autosomal dominant nonsyndromic hearing loss 20.

What condition is associated with ACTG1 p.Phe262Leu (c.786C>G)?

ACTG1 p.Phe262Leu (c.786C>G) is associated with autosomal dominant nonsyndromic hearing loss 20 (ClinVar).

How common is ACTG1 p.Phe262Leu (c.786C>G) in the general population?

ACTG1 p.Phe262Leu (c.786C>G) is ultra-rare (popmax 0.066%, mid) (gnomAD).

What do computational predictors say about ACTG1 p.Phe262Leu (c.786C>G)?

AlphaMissense predicts likely pathogenic (score 0.9932) — an in-silico prediction, not a clinical call.

ACTG1 p.Phe262Leu

c.786C>G · rs1555666611 · VCV2438842

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9932 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nonsyndromic hearing loss 20

Computational evidence

Protein change
AlphaMissense	0.9932	likely pathogenic
REVEL	0.944	strongly pathogenic-leaning
SaProt	LLR -12.93	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 5	GERP -0.47, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 265 bp · p 0.016 · regional, not allelic
Overall
CADD	26.1	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 0.066% Middle Eastern · 4/6,062 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.000479% 7/1,461,376 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)	0.000169%	590,016

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.Phe262Leu
Coding: c.786C>G
MANE Select: NM_001614
dbSNP: rs1555666611
Type: single nucleotide variant
Location: chr17:81511204 (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

autosomal dominant nonsyndromic hearing loss 20 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-phe262leu (accessed [today's date]).

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