Is CAPN9 p.Val331Ala (c.992T>C) pathogenic?

CAPN9 p.Val331Ala (c.992T>C) is classified Uncertain significance in CAPN9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-06). AlphaMissense: likely benign (0.3012); Ultra-rare (popmax 0.0167%, mid).

How common is CAPN9 p.Val331Ala (c.992T>C) in the general population?

CAPN9 p.Val331Ala (c.992T>C) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about CAPN9 p.Val331Ala (c.992T>C)?

AlphaMissense predicts likely benign (score 0.3012) — an in-silico prediction, not a clinical call.

CAPN9 p.Val331Ala

c.992T>C · VCV3484870

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3012 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3012	likely benign
REVEL	0.782	moderately pathogenic-leaning
SaProt	LLR -9.80	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 5.5	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 54 kb · p 0.54 · regional, not allelic
Overall
CADD	25.7	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 0.0167% Middle Eastern · 1/5,980 alleles

Filtering AF 0.00664% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00616%

Overall 0.00706% 114/1,613,740 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.879%	114
Middle Easterngrpmax	0.0167%	5,980
Remaining individualsnot grpmax-eligible	0.0096%	10,412
European (non-Finnish)	0.00797%	12,553
Admixed American	0.00667%	14,999
African / African-American	0.00134%	74,884

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CAPN9
Protein: p.Val331Ala
Coding: c.992T>C
MANE Select: NM_006615
Type: single nucleotide variant
Location: chr1:230779011 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.14 · 2 PDB
Residue 331: the calpain catalytic domain; a β-strand

Full CAPN9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN9 p.Ala101= Likely benign ★★ same type
CAPN9 c.1657+2T>G Uncertain significance ★ same type
CAPN9 p.Ala255Thr Uncertain significance ★ ⚠ same type
CAPN9 p.Ala345Val Uncertain significance ★ ⚠ same type
CAPN9 p.Ala525Asp Uncertain significance ★ ⚠ same type
CAPN9 p.Ala531Thr Uncertain significance ★ ⚠ same type
CAPN9 p.Ala605Thr Uncertain significance ★ ⚠ same type
CAPN9 p.Arg115Gly 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/capn9-p-val331ala (accessed [today's date]).

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