Is ACTB p.Leu140= (c.420A>G) pathogenic?

ACTB p.Leu140= (c.420A>G) is classified Benign/Likely benign in ACTB (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-03-01). Rare (popmax 0.475%, afr); Associated with Baraitser-Winter syndrome 1.

What condition is associated with ACTB p.Leu140= (c.420A>G)?

ACTB p.Leu140= (c.420A>G) is associated with Baraitser-Winter syndrome 1, developmental malformations-deafness-dystonia syndrome (ClinVar).

How common is ACTB p.Leu140= (c.420A>G) in the general population?

ACTB p.Leu140= (c.420A>G) is rare (popmax 0.475%, afr) (gnomAD).

ACTB p.Leu140=

c.420A>G · rs13447405 · VCV290841

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.475%, afr)

Conditions

Baraitser-Winter syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -1.6, phastCons 1
Overall
CADD	12.54	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.475% African / African-American · 356/75,024 alleles

Filtering AF 0.434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.418%

Overall 0.0266% 430/1,613,932 alleles · rare exomes 225/1,461,668 · genomes 205/152,264 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.475%	211
Admixed American	0.05%	2,001
Remaining individualsnot grpmax-eligible	0.0384%	2,604
South Asian	0.00329%	30,361
Finnishnot grpmax-eligible	0.00157%	63,814
European (non-Finnish)	0.00136%	73,752

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.Leu140=
Coding: c.420A>G
MANE Select: NM_001101
dbSNP: rs13447405
Type: single nucleotide variant
Location: chr7:5528663 (GRCh38)
Gene constraint: LOEUF 0.193 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 95.31 · 93 PDB
Residue 140: 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

Also linked: developmental malformations-deafness-dystonia syndrome

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-leu140 (accessed [today's date]).

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