Is CAPN1 p.Pro63Leu (c.188C>T) pathogenic?

CAPN1 p.Pro63Leu (c.188C>T) is classified Uncertain significance in CAPN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-10). AlphaMissense: ambiguous (0.4429); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CAPN1 p.Pro63Leu (c.188C>T)?

CAPN1 p.Pro63Leu (c.188C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CAPN1 p.Pro63Leu (c.188C>T) in the general population?

CAPN1 p.Pro63Leu (c.188C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CAPN1 p.Pro63Leu (c.188C>T)?

AlphaMissense predicts ambiguous (score 0.4429) — an in-silico prediction, not a clinical call.

CAPN1 p.Pro63Leu

c.188C>T · rs1184269173 · VCV1899664

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4429 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,605,984)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4429	ambiguous
REVEL	0.479	indeterminate
SaProt	LLR -8.92	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 29 kb · p 4.3e-06 · regional, not allelic
Overall
CADD	28.2	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

No allele count reported in gnomAD v4.1 (AN 1,605,984). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CAPN1
Protein: p.Pro63Leu
Coding: c.188C>T
MANE Select: NM_005186
dbSNP: rs1184269173
Type: single nucleotide variant
Location: chr11:65182889 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 63: the calpain catalytic domain

Full CAPN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CAPN1 p.Pro63= Likely benign ★★ same residue
CAPN1 p.Arg104His Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg293Gln Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg293Trp Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg347Cys Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg347His Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg48Gln Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg581Gln Uncertain significance ★★ ⚠ 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/capn1-p-pro63leu (accessed [today's date]).

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