Is ACTB p.Ile341Leu (c.1021A>C) pathogenic?

ACTB p.Ile341Leu (c.1021A>C) is classified Uncertain significance in ACTB (ClinVar, Single submitter, 1 submitter; last evaluated 2015-10-28). AlphaMissense: likely pathogenic (0.9675); Absent from gnomAD v4.1.

How common is ACTB p.Ile341Leu (c.1021A>C) in the general population?

ACTB p.Ile341Leu (c.1021A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTB p.Ile341Leu (c.1021A>C)?

AlphaMissense predicts likely pathogenic (score 0.9675) — an in-silico prediction, not a clinical call.

ACTB p.Ile341Leu

c.1021A>C · rs886041305 · VCV279990

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9675 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9675	likely pathogenic
REVEL	0.699	pathogenic-leaning
SaProt	LLR -13.45	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 0.92, phastCons 1
Regional constraint	o/e 0.06	constrained · MANE · 132 bp · p 1.9e-13 · regional, not allelic
Overall
CADD	24.3	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: ACTB
Protein: p.Ile341Leu
Coding: c.1021A>C
MANE Select: NM_001101
dbSNP: rs886041305
Type: single nucleotide variant
Location: chr7:5527855 (GRCh38)
Gene constraint: LOEUF 0.193 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 95.31 · 93 PDB
Residue 341: a UniProt-annotated variant site (in thc8; likely pathogenic); an α-helix

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

Similar variants

ACTB p.Ile341Val Likely pathogenic ★★ same residue
ACTB p.Ile341= Benign ★★ same residue
ACTB p.Ala22Thr Likely pathogenic ★★ same type
ACTB p.Ala7Thr Likely pathogenic ★★ same type
ACTB p.Arg147Cys Pathogenic ★★ same type
ACTB p.Arg183Trp Pathogenic ★★ same type
ACTB p.Arg196Cys Pathogenic ★★ same type
ACTB p.Arg196His Pathogenic ★★ same type

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/actb-p-ile341leu (accessed [today's date]).

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