Is CAPN9 p.Arg368His (c.1103G>A) pathogenic?

CAPN9 p.Arg368His (c.1103G>A) is classified Uncertain significance in CAPN9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-08). AlphaMissense: likely pathogenic (0.7055); Ultra-rare (popmax 0.0419%, mid).

How common is CAPN9 p.Arg368His (c.1103G>A) in the general population?

CAPN9 p.Arg368His (c.1103G>A) is ultra-rare (popmax 0.0419%, mid) (gnomAD).

What do computational predictors say about CAPN9 p.Arg368His (c.1103G>A)?

AlphaMissense predicts likely pathogenic (score 0.7055) — an in-silico prediction, not a clinical call.

CAPN9 p.Arg368His

c.1103G>A · rs144137595 · VCV3137192

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7055 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0419%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7055	likely pathogenic
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -13.92	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	32.0	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 0.0419% Middle Eastern · 2/4,770 alleles

Filtering AF 0.00737% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00447%

Overall 0.00478% 77/1,612,146 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0419%	2,385
Admixed American	0.00667%	15,002
European (non-Finnish)	0.00602%	16,617

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.Arg368His
Coding: c.1103G>A
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.Arg368Leu 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-arg368his (accessed [today's date]).

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