Is ACTN3 p.Lys96Asn (c.288A>T) pathogenic?

ACTN3 p.Lys96Asn (c.288A>T) is classified Uncertain significance in ACTN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-16). AlphaMissense: likely pathogenic (0.922); Very rare (popmax 0.000254%, nfe).

How common is ACTN3 p.Lys96Asn (c.288A>T) in the general population?

ACTN3 p.Lys96Asn (c.288A>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ACTN3 p.Lys96Asn (c.288A>T)?

AlphaMissense predicts likely pathogenic (score 0.922) — an in-silico prediction, not a clinical call.

ACTN3 p.Lys96Asn

c.288A>T · rs1271468945 · VCV3142051

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.922 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.922	likely pathogenic
SaProt	LLR -8.21	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -3.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,650 bp · p 0.64 · regional, not allelic
Overall
CADD	22.2	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 0.000254% European (non-Finnish) · 3/1,179,944 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,730 alleles · very rare

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: ACTN3
Protein: p.Lys96Asn
Coding: c.288A>T
MANE Select: NM_001104
dbSNP: rs1271468945
Type: single nucleotide variant
Location: chr11:66551553 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.61 · 3 PDB
Residue 96: the calponin-homology (ch) 1 domain; the 'actin-binding' region

Full ACTN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTN3 p.Lys96= Likely benign ★ same residue
ACTN3 p.Ala115Asp Uncertain significance ★ ⚠ same type
ACTN3 p.Ala149Thr Uncertain significance ★ ⚠ same type
ACTN3 p.Ala251Thr Uncertain significance ★ ⚠ same type
ACTN3 p.Ala410Pro Uncertain significance ★ ⚠ same type
ACTN3 p.Ala410Val Uncertain significance ★ ⚠ same type
ACTN3 p.Ala460Val Uncertain significance ★ ⚠ same type
ACTN3 p.Ala469Gly 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/actn3-p-lys96asn (accessed [today's date]).

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