Is ACTB p.Arg147His (c.440G>A) pathogenic?

ACTB p.Arg147His (c.440G>A) is classified Uncertain significance in ACTB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely pathogenic (0.9946); Very rare (popmax 8.47e-05%, nfe); Associated with Baraitser-Winter syndrome 1.

What condition is associated with ACTB p.Arg147His (c.440G>A)?

ACTB p.Arg147His (c.440G>A) is associated with Baraitser-Winter syndrome 1 (ClinVar).

How common is ACTB p.Arg147His (c.440G>A) in the general population?

ACTB p.Arg147His (c.440G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ACTB p.Arg147His (c.440G>A)?

AlphaMissense predicts likely pathogenic (score 0.9946) — an in-silico prediction, not a clinical call.

ACTB p.Arg147His

c.440G>A · rs2533847883 · VCV2693728

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9946 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Baraitser-Winter syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9946	likely pathogenic
REVEL	0.947	strongly pathogenic-leaning
SaProt	LLR -12.06	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 3.4	GERP 0.67, phastCons 1
Regional constraint	o/e 0.11	constrained · MANE · 1,149 bp · p 1.6e-51 · regional, not allelic
Overall
CADD	33.0	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 8.47e-05% European (non-Finnish) · 1/1,180,022 alleles

Overall 6.84e-05% 1/1,461,670 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: ACTB
Protein: p.Arg147His
Coding: c.440G>A
MANE Select: NM_001101
dbSNP: rs2533847883
Type: single nucleotide variant
Location: chr7:5528643 (GRCh38)
Gene constraint: LOEUF 0.193 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 95.31 · 93 PDB
Residue 147: a UniProt-annotated variant site (in bns and csmh; also found in isolated non-syndromic becker nevi; somatic variant); a UniProt-annotated variant site (in csmh; also found in isolated non-syndromic becker nevi; somatic variant)

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

Disease context

Baraitser-Winter syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACTB p.Arg147Cys Pathogenic ★★ same residue
ACTB p.Arg147Ser Pathogenic ★ same residue
ACTB p.Ala22Thr Likely pathogenic ★★ same condition
ACTB p.Ala7Thr Likely pathogenic ★★ same condition
ACTB p.Arg183Trp Pathogenic ★★ same condition
ACTB p.Arg196Cys Pathogenic ★★ same condition
ACTB p.Arg196His Pathogenic ★★ same condition
ACTB p.Arg196Leu 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/actb-p-arg147his (accessed [today's date]).

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