Is CAPN13 p.Ala90Ser (c.268G>T) pathogenic?

CAPN13 p.Ala90Ser (c.268G>T) is classified Uncertain significance in CAPN13 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-10). AlphaMissense: likely benign (0.1788); Rare (popmax 0.116%, mid).

How common is CAPN13 p.Ala90Ser (c.268G>T) in the general population?

CAPN13 p.Ala90Ser (c.268G>T) is rare (popmax 0.116%, mid) (gnomAD).

What do computational predictors say about CAPN13 p.Ala90Ser (c.268G>T)?

AlphaMissense predicts likely benign (score 0.1788) — an in-silico prediction, not a clinical call.

CAPN13 p.Ala90Ser

c.268G>T · rs780083368 · VCV2371037

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1788 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.116%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1788	likely benign
REVEL	0.325	indeterminate
SaProt	LLR -5.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 1.2, phastCons 0.71
Regional constraint	o/e 1.05	unconstrained · MANE · 57 kb · p 0.12 · regional, not allelic
Overall
CADD	20.4	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 0.116% Middle Eastern · 7/6,042 alleles

Filtering AF 0.0543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0385%

Overall 0.00394% 62/1,573,606 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.116%	863
Admixed American	0.0406%	2,465
Remaining individualsnot grpmax-eligible	0.00328%	30,518
European (non-Finnish)	0.00268%	37,354

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: CAPN13
Protein: p.Ala90Ser
Coding: c.268G>T
MANE Select: NM_144575
dbSNP: rs780083368
Type: single nucleotide variant
Location: chr2:30777570 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.25 · 1 PDB
Residue 90: the calpain catalytic domain

Full CAPN13 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN13 p.Ala172Ser Uncertain significance ★ ⚠ same type
CAPN13 p.Ala215Ser Uncertain significance ★ ⚠ same type
CAPN13 p.Ala2Val Uncertain significance ★ ⚠ same type
CAPN13 p.Ala326Val Uncertain significance ★ ⚠ same type
CAPN13 p.Ala460Gly Uncertain significance ★ ⚠ same type
CAPN13 p.Ala510Pro Uncertain significance ★ ⚠ same type
CAPN13 p.Ala564Val Uncertain significance ★ ⚠ same type
CAPN13 p.Arg109Gly 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/capn13-p-ala90ser (accessed [today's date]).

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