Is ACTB p.Lys215= (c.645G>A) pathogenic?

ACTB p.Lys215= (c.645G>A) is classified Likely benign in ACTB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-19). Ultra-rare (popmax 0.0853%, afr); Associated with Baraitser-Winter syndrome 1.

What condition is associated with ACTB p.Lys215= (c.645G>A)?

ACTB p.Lys215= (c.645G>A) is associated with Baraitser-Winter syndrome 1, developmental malformations-deafness-dystonia syndrome (ClinVar).

How common is ACTB p.Lys215= (c.645G>A) in the general population?

ACTB p.Lys215= (c.645G>A) is ultra-rare (popmax 0.0853%, afr) (gnomAD).

ACTB p.Lys215=

c.645G>A · rs145017784 · VCV511115

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0853%, 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 3.3	GERP 0.66, phastCons 1
Overall
CADD	13.34	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0853% African / African-American · 64/75,072 alleles

Filtering AF 0.0685% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0624%

Overall 0.00489% 79/1,614,140 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0853%	1,173
South Asian	0.011%	9,109
Remaining individualsnot grpmax-eligible	0.0048%	20,837
European (non-Finnish)	0.000169%	590,023

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.Lys215=
Coding: c.645G>A
MANE Select: NM_001101
dbSNP: rs145017784
Type: single nucleotide variant
Location: chr7:5528438 (GRCh38)
Gene constraint: LOEUF 0.193 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 95.31 · 93 PDB
Residue 215: 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.Lys215Asn Uncertain significance ★ ⚠ same residue
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

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-lys215 (accessed [today's date]).

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