CAPN1

Chr 11AR

calpain 1

Also known as: CANP, CANP1, CANPL1, SPG76, muCANP, muCL

NCBI Gene: 823 ENSG00000014216 UniProt: P07384 OMIM: 114220

Calpain 1 is a calcium-activated cysteine protease that catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. Mutations cause spastic paraplegia 76, an autosomal recessive disorder affecting the corticospinal tracts and motor function. The gene shows low constraint against loss-of-function variants (pLI near 0), consistent with the recessive inheritance pattern observed clinically.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The calpains, calcium-activated neutral proteases, are nonlysosomal, intracellular cysteine proteases. The mammalian calpains include ubiquitous, stomach-specific, and muscle-specific proteins. The ubiquitous enzymes consist of heterodimers with distinct large, catalytic subunits associated with a common small, regulatory subunit. This gene encodes the large subunit of the ubiquitous enzyme, calpain 1. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.711 OMIM phenotype

Clinical Summary— CAPN1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

53 unique Pathogenic / Likely Pathogenic· 161 VUS of 397 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.71LOEUF

pLI 0.000

Z-score 3.16

OE 0.50 (0.36–0.71)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.68Z-score

OE missense 0.78 (0.72–0.85)

369 obs / 471.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.36–0.71)

0≤0.351.4

Missense OE?0.78 (0.72–0.85)

0≤0.61.4

Synonymous OE?0.77

0≤1.21.6

LoF obs/exp: 23 / 46.1Missense obs/exp: 369 / 471.9Syn Z: 2.48

This gene — mechanism propensity

0.6842th %ile

GOF

0.6736th %ile

LOF

0.2288th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

397 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36

Likely Pathogenic17

VUS161

Likely Benign115

Benign33

Conflicting5

Pathogenic

Likely Pathogenic

161

VUS

115

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	29	5	2	0	36
Likely Pathogenic	15	1	1	0	17
VUS	1	154	6	0	161
Likely Benign	0	10	49	56	115
Benign	0	2	23	8	33
Conflicting	—				5
Total	45	172	81	64	367

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

9 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap CAPN1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →