Is ACTG2 p.Asn253Ser (c.758A>G) pathogenic?

ACTG2 p.Asn253Ser (c.758A>G) is classified Uncertain significance in ACTG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-15). AlphaMissense: likely benign (0.2404); Ultra-rare (popmax 0.0133%, sas); Associated with Inborn genetic diseases.

What condition is associated with ACTG2 p.Asn253Ser (c.758A>G)?

ACTG2 p.Asn253Ser (c.758A>G) is associated with Inborn genetic diseases (ClinVar).

How common is ACTG2 p.Asn253Ser (c.758A>G) in the general population?

ACTG2 p.Asn253Ser (c.758A>G) is ultra-rare (popmax 0.0133%, sas) (gnomAD).

What do computational predictors say about ACTG2 p.Asn253Ser (c.758A>G)?

AlphaMissense predicts likely benign (score 0.2404) — an in-silico prediction, not a clinical call.

ACTG2 p.Asn253Ser

c.758A>G · rs760143686 · VCV3141279

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2404 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2404	likely benign
REVEL	0.623	indeterminate
SaProt	LLR -11.66	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2.3, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 18 kb · p 3.5e-30 · regional, not allelic
Overall
CADD	24.6	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 0.0133% South Asian · 12/90,454 alleles

Filtering AF 0.00755% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00597%

Overall 0.00106% 17/1,607,488 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0133%	7,538
Admixed American	0.00503%	19,875
European (non-Finnish)	0.00017%	587,755

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: ACTG2
Protein: p.Asn253Ser
Coding: c.758A>G
MANE Select: NM_001615
dbSNP: rs760143686
Type: single nucleotide variant
Location: chr2:73914824 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI 0.28 (gnomAD)
Structure: AlphaFold pLDDT 95.46 · 4 PDB

Full ACTG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACTG2 p.Arg178Leu Pathogenic ★★ same condition
ACTG2 p.Ala221Val Uncertain significance ★ ⚠ same condition
ACTG2 p.His102Tyr Uncertain significance ★ ⚠ same condition
ACTG2 p.His88Arg Uncertain significance ★ ⚠ same condition
ACTG2 p.Ile330Met Uncertain significance ★ ⚠ same condition
ACTG2 p.Lys374Arg Uncertain significance ★ ⚠ same condition
ACTG2 p.Pro71Arg Uncertain significance ★ ⚠ same condition
ACTG2 p.Ser142Cys Uncertain significance ★ ⚠ 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/actg2-p-asn253ser (accessed [today's date]).

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