Is CAPN15 p.Gln403Arg (c.1208A>G) pathogenic?

CAPN15 p.Gln403Arg (c.1208A>G) is classified Uncertain significance in CAPN15 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-14). AlphaMissense: likely benign (0.0619); Ultra-rare (popmax 0.0141%, sas).

How common is CAPN15 p.Gln403Arg (c.1208A>G) in the general population?

CAPN15 p.Gln403Arg (c.1208A>G) is ultra-rare (popmax 0.0141%, sas) (gnomAD).

What do computational predictors say about CAPN15 p.Gln403Arg (c.1208A>G)?

AlphaMissense predicts likely benign (score 0.0619) — an in-silico prediction, not a clinical call.

CAPN15 p.Gln403Arg

c.1208A>G · VCV4648111

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0619 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0141%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0619	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -5.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -1.4, phastCons 0.98
Regional constraint	o/e 1.14	unconstrained · MANE · 2,296 bp · p 0.00013 · regional, not allelic
Overall
CADD	1.591	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0141% South Asian · 12/85,406 alleles

Filtering AF 0.00807% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00629%

Overall 0.00103% 16/1,557,768 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0141%	7,117
Remaining individualsnot grpmax-eligible	0.00166%	60,234
African / African-American	0.00136%	73,354
European (non-Finnish)	0.000173%	576,472

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: CAPN15
Protein: p.Gln403Arg
Coding: c.1208A>G
MANE Select: NM_005632
Type: single nucleotide variant
Location: chr16:548046 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.65

Full CAPN15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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CAPN15 p.Glu776Ala Uncertain significance ★★ ⚠ same type
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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/capn15-p-gln403arg (accessed [today's date]).

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