Is CAPN1 p.Leu168Pro (c.503T>C) pathogenic?

CAPN1 p.Leu168Pro (c.503T>C) is classified Uncertain significance in CAPN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-01). AlphaMissense: likely pathogenic (0.9985); Very rare (popmax 0.00213%, nfe).

How common is CAPN1 p.Leu168Pro (c.503T>C) in the general population?

CAPN1 p.Leu168Pro (c.503T>C) is very rare (popmax 0.00213%, nfe) (gnomAD).

What do computational predictors say about CAPN1 p.Leu168Pro (c.503T>C)?

AlphaMissense predicts likely pathogenic (score 0.9985) — an in-silico prediction, not a clinical call.

CAPN1 p.Leu168Pro

c.503T>C · VCV3771883

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9985 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00213%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9985	likely pathogenic · top 4% in CAPN1
REVEL	0.685	pathogenic-leaning
SaProt	LLR -15.93	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 29 kb · p 4.3e-06 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00213% European (non-Finnish) · 25/1,172,640 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00124%

Overall 0.00173% 25/1,446,614 alleles · very rare

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: CAPN1
Protein: p.Leu168Pro
Coding: c.503T>C
MANE Select: NM_005186
Type: single nucleotide variant
Location: chr11:65185963 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 168: the calpain catalytic domain; a β-strand

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

Similar variants

CAPN1 c.1605+5G>A Pathogenic/Likely pathogenic ★★ same type
CAPN1 c.267+2T>C Pathogenic/Likely pathogenic ★★ same type
CAPN1 c.338-1G>A Pathogenic ★★ same type
CAPN1 c.759+1G>A Pathogenic ★★ same type
CAPN1 c.843+1G>C Pathogenic/Likely pathogenic ★★ same type
CAPN1 c.929+2T>A Likely pathogenic ★★ same type
CAPN1 p.Arg285Ter Pathogenic/Likely pathogenic ★★ same type
CAPN1 p.Arg385Ter Pathogenic/Likely pathogenic ★★ 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/capn1-p-leu168pro (accessed [today's date]).

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