Is ACTBL2 p.Arg178Leu (c.533G>T) pathogenic?

ACTBL2 p.Arg178Leu (c.533G>T) is classified Uncertain significance in ACTBL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-14). AlphaMissense: likely pathogenic (0.8039); Ultra-rare (popmax 0.033%, mid).

How common is ACTBL2 p.Arg178Leu (c.533G>T) in the general population?

ACTBL2 p.Arg178Leu (c.533G>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about ACTBL2 p.Arg178Leu (c.533G>T)?

AlphaMissense predicts likely pathogenic (score 0.8039) — an in-silico prediction, not a clinical call.

ACTBL2 p.Arg178Leu

c.533G>T · rs200576412 · VCV2231626

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8039 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8039	likely pathogenic
REVEL	0.883	moderately pathogenic-leaning
SaProt	LLR -14.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 1, phastCons 0.98
Regional constraint	o/e 1.08	unconstrained · MANE · 1,127 bp · p 0.086 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.0013% 21/1,614,052 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
European (non-Finnish)	0.00161%	62,106

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.Arg178Leu
Coding: c.533G>T
MANE Select: NM_001017992
dbSNP: rs200576412
Type: single nucleotide variant
Location: chr5:57482175 (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.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-arg178leu (accessed [today's date]).

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