Is ACTBL2 p.Cys53Tyr (c.158G>A) pathogenic?

ACTBL2 p.Cys53Tyr (c.158G>A) is classified Uncertain significance in ACTBL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: likely benign (0.2028); Ultra-rare (popmax 0.0183%, amr).

How common is ACTBL2 p.Cys53Tyr (c.158G>A) in the general population?

ACTBL2 p.Cys53Tyr (c.158G>A) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about ACTBL2 p.Cys53Tyr (c.158G>A)?

AlphaMissense predicts likely benign (score 0.2028) — an in-silico prediction, not a clinical call.

ACTBL2 p.Cys53Tyr

c.158G>A · VCV4637090

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2028 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2028	likely benign
REVEL	0.426	indeterminate
SaProt	LLR -7.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.051, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 1,127 bp · p 0.086 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0183% Admixed American · 11/60,010 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.00366% 59/1,613,976 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,455
Middle Eastern	0.0164%	6,082
South Asian	0.0143%	7,002
European (non-Finnish)	0.00288%	34,707

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: ACTBL2
Protein: p.Cys53Tyr
Coding: c.158G>A
MANE Select: NM_001017992
Type: single nucleotide variant
Location: chr5:57482550 (GRCh38)
Gene constraint: LOEUF 1.624 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.97

Full ACTBL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTBL2 p.Ala171Pro Uncertain significance ★ ⚠ same type
ACTBL2 p.Ala171Ser Uncertain significance ★ ⚠ same type
ACTBL2 p.Ala171Val Uncertain significance ★ ⚠ same type
ACTBL2 p.Ala27Asp Uncertain significance ★ ⚠ same type
ACTBL2 p.Ala296Val Uncertain significance ★ ⚠ same type
ACTBL2 p.Ala30Ser Uncertain significance ★ ⚠ same type
ACTBL2 p.Ala322Thr Uncertain significance ★ ⚠ same type
ACTBL2 p.Arg178Leu Uncertain significance ★ ⚠ same type

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/actbl2-p-cys53tyr (accessed [today's date]).

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