Is CAPN15 p.Arg669Cys (c.2005C>T) pathogenic?

CAPN15 p.Arg669Cys (c.2005C>T) is classified Uncertain significance in CAPN15 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-29). AlphaMissense: ambiguous (0.4267); Very rare (popmax 0.0065%, nfe).

How common is CAPN15 p.Arg669Cys (c.2005C>T) in the general population?

CAPN15 p.Arg669Cys (c.2005C>T) is very rare (popmax 0.0065%, nfe) (gnomAD).

What do computational predictors say about CAPN15 p.Arg669Cys (c.2005C>T)?

AlphaMissense predicts ambiguous (score 0.4267) — an in-silico prediction, not a clinical call.

CAPN15 p.Arg669Cys

c.2005C>T · VCV4218843

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4267 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0065%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4267	ambiguous
REVEL	0.628	indeterminate
SaProt	LLR -7.59	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 4,055 bp · p 0.036 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0065% European (non-Finnish) · 76/1,169,822 alleles

Filtering AF 0.00532% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00486%

Overall 0.00515% 82/1,592,650 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0065%	15,392
Ashkenazi Jewishnot grpmax-eligible	0.00342%	29,280
Remaining individualsnot grpmax-eligible	0.00325%	30,771
Finnishnot grpmax-eligible	0.00164%	60,912
African / African-American	0.00135%	74,276
South Asian	0.00113%	88,122

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.Arg669Cys
Coding: c.2005C>T
MANE Select: NM_005632
Type: single nucleotide variant
Location: chr16:549777 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.65
Residue 669: the calpain catalytic domain

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

Similar variants

CAPN15 p.Arg669His Uncertain significance ★ ⚠ 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-arg669cys (accessed [today's date]).

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