Is CAPN9 p.Arg368Leu (c.1103G>T) pathogenic?

CAPN9 p.Arg368Leu (c.1103G>T) is classified Uncertain significance in CAPN9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely pathogenic (0.8884); Ultra-rare (popmax 0.0487%, nfe).

How common is CAPN9 p.Arg368Leu (c.1103G>T) in the general population?

CAPN9 p.Arg368Leu (c.1103G>T) is ultra-rare (popmax 0.0487%, nfe) (gnomAD).

What do computational predictors say about CAPN9 p.Arg368Leu (c.1103G>T)?

AlphaMissense predicts likely pathogenic (score 0.8884) — an in-silico prediction, not a clinical call.

CAPN9 p.Arg368Leu

c.1103G>T · rs144137595 · VCV3137193

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8884 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0487%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8884	likely pathogenic
REVEL	0.876	moderately pathogenic-leaning
SaProt	LLR -12.37	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 6.8	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 54 kb · p 0.54 · regional, not allelic
Overall
CADD	31.0	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 0.0487% European (non-Finnish) · 574/1,179,810 alleles

Filtering AF 0.0453% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.044%

Overall 0.0386% 623/1,612,034 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0487%	2,055
Middle Eastern	0.0417%	2,396
Remaining individualsnot grpmax-eligible	0.0385%	2,596
African / African-American	0.016%	6,235
Admixed American	0.015%	6,665
Finnishnot grpmax-eligible	0.00313%	31,991

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.Arg368Leu
Coding: c.1103G>T
MANE Select: NM_006615
dbSNP: rs144137595
Type: single nucleotide variant
Location: chr1:230779122 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.14 · 2 PDB
Residue 368: the 'domain iii' region

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

Similar variants

CAPN9 p.Arg368Cys Uncertain significance ★ ⚠ same residue
CAPN9 p.Arg368His Uncertain significance ★ ⚠ same residue
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

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-arg368leu (accessed [today's date]).

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