Is CAPN2 p.Tyr335Ser (c.1004A>C) pathogenic?

CAPN2 p.Tyr335Ser (c.1004A>C) is classified Uncertain significance in CAPN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely pathogenic (0.983); Ultra-rare (popmax 0.0296%, sas).

How common is CAPN2 p.Tyr335Ser (c.1004A>C) in the general population?

CAPN2 p.Tyr335Ser (c.1004A>C) is ultra-rare (popmax 0.0296%, sas) (gnomAD).

What do computational predictors say about CAPN2 p.Tyr335Ser (c.1004A>C)?

AlphaMissense predicts likely pathogenic (score 0.983) — an in-silico prediction, not a clinical call.

CAPN2 p.Tyr335Ser

c.1004A>C · VCV4218887

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.983 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0296%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.983	likely pathogenic
REVEL	0.9	moderately pathogenic-leaning
SaProt	LLR -15.83	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 7.9	GERP 0.31, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 62 kb · p 0.00029 · regional, not allelic
Overall
CADD	27.3	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 0.0296% South Asian · 27/91,084 alleles

Filtering AF 0.0208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.00186% 30/1,614,112 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0296%	3,373
Remaining individualsnot grpmax-eligible	0.0048%	20,837

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: CAPN2
Protein: p.Tyr335Ser
Coding: c.1004A>C
MANE Select: NM_001748
Type: single nucleotide variant
Location: chr1:223752825 (GRCh38)
Gene constraint: LOEUF 1.026 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48 · 3 PDB
Residue 335: the calpain catalytic domain

Full CAPN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN2 p.Tyr335Cys Uncertain significance ★ ⚠ same residue
CAPN2 p.Ala248Thr Uncertain significance ★★ ⚠ same type
CAPN2 p.Gly72Asp Uncertain significance ★★ ⚠ same type
CAPN2 p.Asp48= Benign ★★ same type
CAPN2 p.Lys677Gln Benign ★★ same type
CAPN2 p.Ala101Pro Uncertain significance ★ ⚠ same type
CAPN2 p.Ala171Asp Uncertain significance ★ ⚠ same type
CAPN2 p.Ala194Ser 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/capn2-p-tyr335ser (accessed [today's date]).

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