Is CAPN15 p.Arg407His (c.1220G>A) pathogenic?

CAPN15 p.Arg407His (c.1220G>A) is classified Uncertain significance in CAPN15 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: likely benign (0.0874); Very rare (popmax 0.00583%, nfe).

How common is CAPN15 p.Arg407His (c.1220G>A) in the general population?

CAPN15 p.Arg407His (c.1220G>A) is very rare (popmax 0.00583%, nfe) (gnomAD).

What do computational predictors say about CAPN15 p.Arg407His (c.1220G>A)?

AlphaMissense predicts likely benign (score 0.0874) — an in-silico prediction, not a clinical call.

CAPN15 p.Arg407His

c.1220G>A · VCV4218840

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0874 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00583%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0874	likely benign
REVEL	0.209	benign-leaning
SaProt	LLR -7.76	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 3.8	GERP 1.2, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 2,296 bp · p 0.00013 · regional, not allelic
Overall
CADD	16.91	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 0.00583% European (non-Finnish) · 67/1,148,444 alleles

Filtering AF 0.00466% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00428%

Overall 0.00465% 72/1,549,638 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00583%	17,141
South Asian	0.00474%	21,116
African / African-American	0.00137%	73,106

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.Arg407His
Coding: c.1220G>A
MANE Select: NM_005632
Type: single nucleotide variant
Location: chr16:548058 (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

Similar variants

CAPN15 p.Arg407= Likely benign ★ same residue
CAPN15 c.2192+8C>T Uncertain significance ★★ same type
CAPN15 p.Arg428Trp Uncertain significance ★★ ⚠ same type
CAPN15 p.Arg867Cys Uncertain significance ★★ ⚠ same type
CAPN15 p.Arg867His Uncertain significance ★★ ⚠ same type
CAPN15 p.Cys363Arg Uncertain significance ★★ ⚠ same type
CAPN15 p.Glu776Ala Uncertain significance ★★ ⚠ same type
CAPN15 p.Val489Met 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/capn15-p-arg407his (accessed [today's date]).

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