Is CAPN1 c.929+2T>A pathogenic?

CAPN1 c.929+2T>A is classified Likely pathogenic in CAPN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-29). Ultra-rare (popmax 0.0124%, afr); Associated with autosomal recessive spastic paraplegia type 76.

What condition is associated with CAPN1 c.929+2T>A?

CAPN1 c.929+2T>A is associated with autosomal recessive spastic paraplegia type 76 (ClinVar).

How common is CAPN1 c.929+2T>A in the general population?

CAPN1 c.929+2T>A is ultra-rare (popmax 0.0124%, afr) (gnomAD).

How is Autosomal recessive spastic paraplegia type 76 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CAPN1 c.929+2T>A

rs1356340954 · VCV1029241

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0124%, afr)

Conditions

autosomal recessive spastic paraplegia type 76

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	Δ0.95	donor loss · deltas
Pangolin	Δ0.82	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Non-coding constraint	Z 5.46	1 kb window · o/e 0.68 · regional · uncalibrated
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0124% African / African-American · 9/72,602 alleles

Filtering AF 0.00641% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00481%

Overall 0.000645% 10/1,550,974 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0124%	8,067
Remaining individualsnot grpmax-eligible	0.00166%	60,122

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
Coding: c.929+2T>A
MANE Select: NM_005186
dbSNP: rs1356340954
Type: single nucleotide variant
Location: chr11:65188042 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB

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

Disease context

autosomal recessive spastic paraplegia type 76 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive spastic paraplegia type 76 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult

Similar variants

CAPN1 c.1605+5G>A Pathogenic/Likely pathogenic ★★ same condition
CAPN1 c.267+2T>C Pathogenic/Likely pathogenic ★★ same condition
CAPN1 c.338-1G>A Pathogenic ★★ same condition
CAPN1 c.843+1G>C Pathogenic/Likely pathogenic ★★ same condition
CAPN1 p.Arg285Ter Pathogenic/Likely pathogenic ★★ same condition
CAPN1 p.Arg385Ter Pathogenic/Likely pathogenic ★★ same condition
CAPN1 p.Glu657Ter Pathogenic/Likely pathogenic ★★ same condition
CAPN1 p.Trp335Ter Pathogenic/Likely pathogenic ★★ 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-c-929-plus-2t-a (accessed [today's date]).

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