Is CAPN15 p.Arg428Trp (c.1282C>T) pathogenic?

CAPN15 p.Arg428Trp (c.1282C>T) is classified Uncertain significance in CAPN15 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-22). AlphaMissense: likely benign (0.122); Rare (popmax 0.293%, afr).

How common is CAPN15 p.Arg428Trp (c.1282C>T) in the general population?

CAPN15 p.Arg428Trp (c.1282C>T) is rare (popmax 0.293%, afr) (gnomAD).

What do computational predictors say about CAPN15 p.Arg428Trp (c.1282C>T)?

AlphaMissense predicts likely benign (score 0.122) — an in-silico prediction, not a clinical call.

CAPN15 p.Arg428Trp

c.1282C>T · VCV3368900

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.122 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.293%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.122	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -8.57	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 1.2	GERP 1.2, phastCons 0.49
Regional constraint	o/e 1.14	unconstrained · MANE · 2,296 bp · p 0.00013 · regional, not allelic
Overall
CADD	22.7	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 0.293% African / African-American · 211/72,044 alleles

Filtering AF 0.26% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.248%

Overall 0.0218% 335/1,534,126 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.293%	341
Ashkenazi Jewishnot grpmax-eligible	0.121%	824
Admixed American	0.0219%	4,574
Remaining individualsnot grpmax-eligible	0.0203%	4,915
European (non-Finnish)	0.00578%	17,295
South Asian	0.00247%	40,422
Finnishnot grpmax-eligible	0.00178%	56,290

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.Arg428Trp
Coding: c.1282C>T
MANE Select: NM_005632
Type: single nucleotide variant
Location: chr16:548120 (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.Arg428Gln Likely benign same residue
CAPN15 c.2192+8C>T 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
CAPN15 p.Val841Met 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-arg428trp (accessed [today's date]).

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