Is CAPN9 p.Phe65Ser (c.194T>C) pathogenic?

CAPN9 p.Phe65Ser (c.194T>C) is classified Uncertain significance in CAPN9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-28). AlphaMissense: likely pathogenic (0.7822); Ultra-rare (popmax 0.0153%, nfe).

How common is CAPN9 p.Phe65Ser (c.194T>C) in the general population?

CAPN9 p.Phe65Ser (c.194T>C) is ultra-rare (popmax 0.0153%, nfe) (gnomAD).

What do computational predictors say about CAPN9 p.Phe65Ser (c.194T>C)?

AlphaMissense predicts likely pathogenic (score 0.7822) — an in-silico prediction, not a clinical call.

CAPN9 p.Phe65Ser

c.194T>C · VCV3484871

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7822 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0153%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7822	likely pathogenic
REVEL	0.251	benign-leaning
SaProt	LLR -12.11	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 54 kb · p 0.54 · regional, not allelic
Overall
CADD	26.0	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 0.0153% European (non-Finnish) · 181/1,179,994 alleles

Filtering AF 0.0135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.0119% 192/1,614,082 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0153%	6,519
Remaining individualsnot grpmax-eligible	0.0112%	8,929
Finnishnot grpmax-eligible	0.00469%	21,340
African / African-American	0.00133%	75,014

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.Phe65Ser
Coding: c.194T>C
MANE Select: NM_006615
Type: single nucleotide variant
Location: chr1:230747690 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.14 · 2 PDB
Residue 65: the calpain catalytic domain

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-phe65ser (accessed [today's date]).

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