Is CAPN9 p.Gln402Arg (c.1205A>G) pathogenic?

CAPN9 p.Gln402Arg (c.1205A>G) is classified Uncertain significance in CAPN9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-22). AlphaMissense: likely pathogenic (0.9454); Ultra-rare (popmax 0.0495%, mid).

How common is CAPN9 p.Gln402Arg (c.1205A>G) in the general population?

CAPN9 p.Gln402Arg (c.1205A>G) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about CAPN9 p.Gln402Arg (c.1205A>G)?

AlphaMissense predicts likely pathogenic (score 0.9454) — an in-silico prediction, not a clinical call.

CAPN9 p.Gln402Arg

c.1205A>G · rs542860265 · VCV3137194

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9454 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9454	likely pathogenic · top 9% in CAPN9
REVEL	0.909	moderately pathogenic-leaning
SaProt	LLR -12.87	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 10	GERP 2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 54 kb · p 0.54 · regional, not allelic
Overall
CADD	25.2	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 0.0495% Middle Eastern · 3/6,062 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.00793% 128/1,614,140 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.294%	340
Middle Easterngrpmax	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0304%	3,290
Admixed American	0.00333%	30,013
European (non-Finnish)	0.00136%	73,748
African / African-American	0.00133%	75,038

Ashkenazi Jewish 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.Gln402Arg
Coding: c.1205A>G
MANE Select: NM_006615
dbSNP: rs542860265
Type: single nucleotide variant
Location: chr1:230780269 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.14 · 2 PDB
Residue 402: the 'domain iii' region

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-gln402arg (accessed [today's date]).

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