Is CAPN1 p.Gly208fs (c.618_619del) pathogenic?

CAPN1 p.Gly208fs (c.618619del) is classified Pathogenic in CAPN1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-18). Ultra-rare (popmax 0.015%, amr); Associated with autosomal recessive spastic paraplegia type 76.

What condition is associated with CAPN1 p.Gly208fs (c.618_619del)?

CAPN1 p.Gly208fs (c.618_619del) is associated with autosomal recessive spastic paraplegia type 76 (ClinVar).

How common is CAPN1 p.Gly208fs (c.618_619del) in the general population?

CAPN1 p.Gly208fs (c.618_619del) is ultra-rare (popmax 0.015%, amr) (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.Gly208fs

c.618_619del · rs778722037 · VCV802686

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

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	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.9	GERP 1.3, phastCons 0.99
Overall
CADD	35.0	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 0.015% Admixed American · 9/59,960 alleles

Filtering AF 0.00774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0066%

Overall 0.007% 113/1,613,406 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,662
European (non-Finnish)	0.00848%	11,797
Remaining individualsnot grpmax-eligible	0.00641%	15,612

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.Gly208fs
Coding: c.618_619del
MANE Select: NM_005186
dbSNP: rs778722037
Type: Deletion
Location: chr11:65186197 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 208: the calpain catalytic domain

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.Gly208Asp Pathogenic ★ same residue
CAPN1 p.Arg377fs Pathogenic/Likely pathogenic ★★ same condition
CAPN1 c.843+114del Benign/Likely benign ★★ same condition
CAPN1 p.Pro136fs Pathogenic ★ same condition
CAPN1 p.Gly208Cys Uncertain significance ★ ⚠ same residue
CAPN1 p.Val178_Phe186del Uncertain significance ★ same condition
CAPN1 c.1605+5G>A Pathogenic/Likely pathogenic ★★ same condition
CAPN1 c.267+2T>C 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-gly208fs (accessed [today's date]).

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