Is CAPN1 p.Arg285Ter (c.853C>T) pathogenic?

CAPN1 p.Arg285Ter (c.853C>T) is classified Pathogenic/Likely pathogenic in CAPN1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-10-22). Very rare (popmax 0.000434%, nfe); Associated with CAPN1-related disorder.

What condition is associated with CAPN1 p.Arg285Ter (c.853C>T)?

CAPN1 p.Arg285Ter (c.853C>T) is associated with CAPN1-related disorder, hereditary spastic paraplegia 11, autosomal recessive spastic paraplegia type 76 (ClinVar).

How common is CAPN1 p.Arg285Ter (c.853C>T) in the general population?

CAPN1 p.Arg285Ter (c.853C>T) is very rare (popmax 0.000434%, nfe) (gnomAD).

CAPN1 p.Arg285Ter

c.853C>T · rs1033093801 · VCV489121

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000434%, nfe)

Conditions

CAPN1-related disorder

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 8 of 22
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.22 · evaluated, not missing
Pangolin	Δ0.27	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 3.2	GERP -1.3, phastCons 1
Overall
CADD	37.0	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 0.000434% European (non-Finnish) · 5/1,151,204 alleles

Filtering AF 0.000127% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.3e-05%

Overall 0.000427% 6/1,406,610 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00165%	60,460
European (non-Finnish)grpmax	0.000434%	230,241

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg285Ter
Coding: c.853C>T
MANE Select: NM_005186
dbSNP: rs1033093801
Type: single nucleotide variant
Location: chr11:65187964 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 285: the calpain catalytic domain

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

Disease context

CAPN1-related disorder

Also linked: hereditary spastic paraplegia 11 autosomal recessive spastic paraplegia type 76

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.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-p-arg285ter (accessed [today's date]).

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