Is ACTBL2 p.Ala171Ser (c.511G>T) pathogenic?

ACTBL2 p.Ala171Ser (c.511G>T) is classified Uncertain significance in ACTBL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). AlphaMissense: likely benign (0.1507); Very rare (popmax 0.01%, amr).

How common is ACTBL2 p.Ala171Ser (c.511G>T) in the general population?

ACTBL2 p.Ala171Ser (c.511G>T) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about ACTBL2 p.Ala171Ser (c.511G>T)?

AlphaMissense predicts likely benign (score 0.1507) — an in-silico prediction, not a clinical call.

ACTBL2 p.Ala171Ser

c.511G>T · VCV4001583

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1507 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1507	likely benign
REVEL	0.34	indeterminate
SaProt	LLR -7.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 1,127 bp · p 0.086 · regional, not allelic
Overall
CADD	23.0	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 0.01% Admixed American · 6/60,008 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00173% 28/1,614,040 alleles · very rare exomes 23/1,461,856 · genomes 5/152,184 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,001
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	0.00161%	62,108
African / African-American	0.00133%	74,924

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.Ala171Ser
Coding: c.511G>T
MANE Select: NM_001017992
Type: single nucleotide variant
Location: chr5:57482197 (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 residue
ACTBL2 p.Ala171Val Uncertain significance ★ same residue
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
ACTBL2 p.Arg207Leu 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-ala171ser (accessed [today's date]).

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