Is ACTC1 p.Lys375Arg (c.1124A>G) pathogenic?

ACTC1 p.Lys375Arg (c.1124A>G) is classified Uncertain significance in ACTC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-03-16). AlphaMissense: ambiguous (0.4624); Absent from gnomAD v4.1.

How common is ACTC1 p.Lys375Arg (c.1124A>G) in the general population?

ACTC1 p.Lys375Arg (c.1124A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTC1 p.Lys375Arg (c.1124A>G)?

AlphaMissense predicts ambiguous (score 0.4624) — an in-silico prediction, not a clinical call.

ACTC1 p.Lys375Arg

c.1124A>G · rs869025355 · VCV222483

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4624 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4624	ambiguous
REVEL	0.88	moderately pathogenic-leaning
SaProt	LLR -12.22	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.35	constrained · MANE · 850 bp · p 1.5e-13 · regional, not allelic
Overall
CADD	26.4	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

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: ACTC1
Protein: p.Lys375Arg
Coding: c.1124A>G
dbSNP: rs869025355
Type: single nucleotide variant
Location: chr15:34790422 (GRCh38)

Full ACTC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/actc1-p-lys375arg (accessed [today's date]).

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