Is CAPN1 p.Glu223Ter (c.667G>T) pathogenic?

CAPN1 p.Glu223Ter (c.667G>T) is classified Likely pathogenic in CAPN1 (ClinVar, Single submitter, 1 submitter). Very rare (popmax 0.00223%, eas); Associated with autosomal recessive spastic paraplegia type 76.

What condition is associated with CAPN1 p.Glu223Ter (c.667G>T)?

CAPN1 p.Glu223Ter (c.667G>T) is associated with autosomal recessive spastic paraplegia type 76 (ClinVar).

How common is CAPN1 p.Glu223Ter (c.667G>T) in the general population?

CAPN1 p.Glu223Ter (c.667G>T) is very rare (popmax 0.00223%, eas) (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.Glu223Ter

c.667G>T · rs779787878 · VCV2584813

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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 6 of 22
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.3, phastCons 1
Overall
CADD	39.0	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 0.00223% East Asian · 1/44,862 alleles

Overall 0.000137% 2/1,461,334 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,862
European (non-Finnish)	8.48e-05%	1,179,682

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.Glu223Ter
Coding: c.667G>T
MANE Select: NM_005186
dbSNP: rs779787878
Type: single nucleotide variant
Location: chr11:65186246 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 223: 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 p.Glu223Lys 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-glu223ter (accessed [today's date]).

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