Is CAPN1 p.Ile148Leu (c.442A>C) pathogenic?

CAPN1 p.Ile148Leu (c.442A>C) is classified Uncertain significance in CAPN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). AlphaMissense: likely benign (0.2141); Ultra-rare (popmax 0.0521%, afr); Associated with Inborn genetic diseases.

What condition is associated with CAPN1 p.Ile148Leu (c.442A>C)?

CAPN1 p.Ile148Leu (c.442A>C) is associated with Inborn genetic diseases (ClinVar).

How common is CAPN1 p.Ile148Leu (c.442A>C) in the general population?

CAPN1 p.Ile148Leu (c.442A>C) is ultra-rare (popmax 0.0521%, afr) (gnomAD).

What do computational predictors say about CAPN1 p.Ile148Leu (c.442A>C)?

AlphaMissense predicts likely benign (score 0.2141) — an in-silico prediction, not a clinical call.

CAPN1 p.Ile148Leu

c.442A>C · VCV3995113

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2141 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0521%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2141	likely benign
REVEL	0.748	pathogenic-leaning
SaProt	LLR -8.85	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2.2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 29 kb · p 4.3e-06 · regional, not allelic
Overall
CADD	25.9	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 0.0521% African / African-American · 39/74,914 alleles

Filtering AF 0.039% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0346%

Overall 0.00248% 40/1,612,652 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0521%	1,921
Remaining individualsnot grpmax-eligible	0.0016%	62,406

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.Ile148Leu
Coding: c.442A>C
MANE Select: NM_005186
Type: single nucleotide variant
Location: chr11:65183578 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 148: the calpain catalytic domain; a β-strand

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.Ile148= 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-ile148leu (accessed [today's date]).

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