Is CAPN1 p.Trp85Ter (c.254G>A) pathogenic?

CAPN1 p.Trp85Ter (c.254G>A) is classified Pathogenic in CAPN1 (ClinVar, Single submitter, 1 submitter). Absent from gnomAD v4.1; Associated with autosomal recessive spastic paraplegia type 76.

What condition is associated with CAPN1 p.Trp85Ter (c.254G>A)?

CAPN1 p.Trp85Ter (c.254G>A) is associated with autosomal recessive spastic paraplegia type 76 (ClinVar).

How common is CAPN1 p.Trp85Ter (c.254G>A) in the general population?

CAPN1 p.Trp85Ter (c.254G>A) is absent from gnomAD v4.1 (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 p.Trp85Ter

c.254G>A · rs1948565964 · VCV986744

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

autosomal recessive spastic paraplegia type 76

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 22
REVEL	0.258	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Overall
CADD	46.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CAPN1
Protein: p.Trp85Ter
Coding: c.254G>A
MANE Select: NM_005186
dbSNP: rs1948565964
Type: single nucleotide variant
Location: chr11:65182955 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 85: the calpain catalytic domain; a β-strand

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 c.929+2T>A 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

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-trp85ter (accessed [today's date]).

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