Is CAPN1 p.Glu447Asp (c.1341G>C) pathogenic?

CAPN1 p.Glu447Asp (c.1341G>C) is classified Pathogenic in CAPN1 (ClinVar, Single submitter, 1 submitter). AlphaMissense: ambiguous (0.3571); Absent from gnomAD v4.1; Associated with autosomal recessive spastic paraplegia type 76.

What condition is associated with CAPN1 p.Glu447Asp (c.1341G>C)?

CAPN1 p.Glu447Asp (c.1341G>C) is associated with autosomal recessive spastic paraplegia type 76 (ClinVar).

How common is CAPN1 p.Glu447Asp (c.1341G>C) in the general population?

CAPN1 p.Glu447Asp (c.1341G>C) 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.

What do computational predictors say about CAPN1 p.Glu447Asp (c.1341G>C)?

AlphaMissense predicts ambiguous (score 0.3571) — an in-silico prediction, not a clinical call.

CAPN1 p.Glu447Asp

c.1341G>C · rs1471188671 · VCV986749

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3571 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

autosomal recessive spastic paraplegia type 76

Computational evidence

Protein change
AlphaMissense	0.3571	ambiguous
REVEL	0.43	indeterminate
SaProt	LLR -9.13	tolerated
Splicing
SpliceAI	Δ0.85	donor loss · deltas
Pangolin	Δ0.83	loss · gain 0.06 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 29 kb · p 4.3e-06 · regional, not allelic
Overall
CADD	26.6	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

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.Glu447Asp
Coding: c.1341G>C
MANE Select: NM_005186
dbSNP: rs1471188671
Type: single nucleotide variant
Location: chr11:65204858 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 447: the 'domain iii' region

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 p.Glu447Gln Uncertain significance ★ ⚠ same residue
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

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-glu447asp (accessed [today's date]).

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