Is ACTBL2 p.Asn281His (c.841A>C) pathogenic?

ACTBL2 p.Asn281His (c.841A>C) is classified Uncertain significance in ACTBL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). AlphaMissense: likely benign (0.0725); Ultra-rare (popmax 0.0245%, eas).

How common is ACTBL2 p.Asn281His (c.841A>C) in the general population?

ACTBL2 p.Asn281His (c.841A>C) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

What do computational predictors say about ACTBL2 p.Asn281His (c.841A>C)?

AlphaMissense predicts likely benign (score 0.0725) — an in-silico prediction, not a clinical call.

ACTBL2 p.Asn281His

c.841A>C · VCV3483395

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0725 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0725	likely benign
REVEL	0.787	moderately pathogenic-leaning
SaProt	LLR -9.81	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 1,127 bp · p 0.086 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0245% East Asian · 11/44,870 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.000744% 12/1,613,924 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,079
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Asn281His
Coding: c.841A>C
MANE Select: NM_001017992
Type: single nucleotide variant
Location: chr5:57481867 (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-asn281his (accessed [today's date]).

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