Is ACTG1 p.Pro333Arg (c.998C>G) pathogenic?

ACTG1 p.Pro333Arg (c.998C>G) is classified Likely pathogenic in ACTG1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-13). AlphaMissense: likely pathogenic (0.9476); Absent from gnomAD v4.1; Associated with ACTG1-related disorder.

What condition is associated with ACTG1 p.Pro333Arg (c.998C>G)?

ACTG1 p.Pro333Arg (c.998C>G) is associated with ACTG1-related disorder (ClinVar).

How common is ACTG1 p.Pro333Arg (c.998C>G) in the general population?

ACTG1 p.Pro333Arg (c.998C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTG1 p.Pro333Arg (c.998C>G)?

AlphaMissense predicts likely pathogenic (score 0.9476) — an in-silico prediction, not a clinical call.

ACTG1 p.Pro333Arg

c.998C>G · rs2544386395 · VCV1810558

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9476 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ACTG1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9476	likely pathogenic ✓ concordant with ClinVar
REVEL	0.841	moderately pathogenic-leaning
SaProt	LLR -14.71	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 7.3	GERP -0.47, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 397 bp · p 8e-16 · regional, not allelic
Overall
CADD	25.8	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: ACTG1
Protein: p.Pro333Arg
Coding: c.998C>G
MANE Select: NM_001614
dbSNP: rs2544386395
Type: single nucleotide variant
Location: chr17:81510820 (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

ACTG1-related disorder

Similar variants

ACTG1 p.His40Tyr Likely pathogenic ★★ same condition
ACTG1 p.Met283Val Likely pathogenic ★★ ⚠ same condition
ACTG1 p.Pro264Leu Pathogenic ★★ same condition
ACTG1 p.Pro32Ser Pathogenic/Likely pathogenic ★★ same condition
ACTG1 p.Pro332Ala Pathogenic/Likely pathogenic ★★ same condition
ACTG1 p.Tyr306Asp Likely pathogenic ★ same condition
ACTG1 p.Tyr337Cys Likely pathogenic ★ same condition
ACTG1 c.985-9T>G Uncertain significance ★ 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-pro333arg (accessed [today's date]).

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