Is CAPN15 p.Pro143Arg (c.428C>G) pathogenic?

CAPN15 p.Pro143Arg (c.428C>G) is classified Benign in CAPN15 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-09-27). AlphaMissense: likely benign (0.0862); Common (popmax 11.6%, afr) — too common for a highly-penetrant pathogenic allele; Associated with CAPN15-related disorder.

What condition is associated with CAPN15 p.Pro143Arg (c.428C>G)?

CAPN15 p.Pro143Arg (c.428C>G) is associated with CAPN15-related disorder (ClinVar).

What do computational predictors say about CAPN15 p.Pro143Arg (c.428C>G)?

AlphaMissense predicts likely benign (score 0.0862) — an in-silico prediction, not a clinical call.

CAPN15 p.Pro143Arg

Q: How common is CAPN15 p.Pro143Arg (c.428C>G) in the general population?

CAPN15 p.Pro143Arg (c.428C>G) is common (popmax 11.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.428C>G · rs112599163 · VCV3038845

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0862 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 11.6%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CAPN15-related disorder

Computational evidence

Protein change
AlphaMissense	0.0862	likely benign
REVEL	0.189	benign-leaning
SaProt	LLR -6.35	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 1.7	GERP 0.14, phastCons 0.004
Regional constraint	o/e 1.14	unconstrained · MANE · 2,296 bp · p 0.00013 · regional, not allelic
Overall
CADD	7.164	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 11.6% African / African-American · 8,445/72,646 alleles

Filtering AF 11.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.3%

Overall 0.639% 9,651/1,509,252 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	11.6%	9
Admixed American	0.934%	107
Remaining individualsnot grpmax-eligible	0.914%	109
Middle Eastern	0.523%	191
Ashkenazi Jewishnot grpmax-eligible	0.273%	367
South Asian	0.0214%	4,662
European (non-Finnish)	0.00961%	10,403

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.Pro143Arg
Coding: c.428C>G
MANE Select: NM_005632
dbSNP: rs112599163
Type: single nucleotide variant
Location: chr16:547266 (GRCh38)
Gene constraint: LOEUF 0.974 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.65
Residue 143: the 'disordered' region

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

Disease context

CAPN15-related disorder

Similar variants

CAPN15 p.Pro494Ser Uncertain significance ★ ⚠ same condition
CAPN15 p.Ser613Leu Conflicting classifications of pathogenicity ★ ⚠ same condition
CAPN15 p.Thr950Ala Uncertain significance ⚠ same condition
CAPN15 p.Ala559= Likely benign same condition
CAPN15 p.Ala817= Likely benign same condition
CAPN15 p.Arg428Gln Likely benign same condition
CAPN15 p.Asn745= Likely benign same condition
CAPN15 p.Asp590= Benign same condition

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-pro143arg (accessed [today's date]).

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