Is ACTB p.Lys336Arg (c.1007A>G) pathogenic?

ACTB p.Lys336Arg (c.1007A>G) is classified Uncertain significance in ACTB (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-18). AlphaMissense: ambiguous (0.3958); Very rare (popmax 0.00134%, afr); Associated with Baraitser-Winter syndrome 1.

What condition is associated with ACTB p.Lys336Arg (c.1007A>G)?

ACTB p.Lys336Arg (c.1007A>G) is associated with Baraitser-Winter syndrome 1 (ClinVar).

How common is ACTB p.Lys336Arg (c.1007A>G) in the general population?

ACTB p.Lys336Arg (c.1007A>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about ACTB p.Lys336Arg (c.1007A>G)?

AlphaMissense predicts ambiguous (score 0.3958) — an in-silico prediction, not a clinical call.

ACTB p.Lys336Arg

c.1007A>G · VCV4338510

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3958 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Baraitser-Winter syndrome 1

Computational evidence

Protein change
AlphaMissense	0.3958	ambiguous
REVEL	0.813	moderately pathogenic-leaning
SaProt	LLR -11.90	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.32	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.06	constrained · MANE · 132 bp · p 1.9e-13 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.00134% African / African-American · 1/74,900 alleles

Overall 0.000124% 2/1,613,930 alleles · very rare exomes 1/1,461,814 · genomes 1/152,116 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,900
European (non-Finnish)	8.47e-05%	1,179,986

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.Lys336Arg
Coding: c.1007A>G
MANE Select: NM_001101
Type: single nucleotide variant
Location: chr7:5527869 (GRCh38)
Gene constraint: LOEUF 0.193 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 95.31 · 93 PDB
Residue 336: an α-helix

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.Ala22Thr Likely pathogenic ★★ same condition
ACTB p.Ala7Thr Likely pathogenic ★★ same condition
ACTB p.Arg147Cys 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
ACTB p.Arg206Gln 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/actb-p-lys336arg (accessed [today's date]).

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