Is CAPN1 p.Arg481Gln (c.1442G>A) pathogenic?

CAPN1 p.Arg481Gln (c.1442G>A) is classified Uncertain significance in CAPN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-06-01). AlphaMissense: likely pathogenic (0.9942); Very rare (popmax 0.00267%, afr); Associated with autosomal recessive spastic paraplegia type 76.

What condition is associated with CAPN1 p.Arg481Gln (c.1442G>A)?

CAPN1 p.Arg481Gln (c.1442G>A) is associated with autosomal recessive spastic paraplegia type 76 (ClinVar).

How common is CAPN1 p.Arg481Gln (c.1442G>A) in the general population?

CAPN1 p.Arg481Gln (c.1442G>A) is very rare (popmax 0.00267%, afr) (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.Arg481Gln (c.1442G>A)?

AlphaMissense predicts likely pathogenic (score 0.9942) — an in-silico prediction, not a clinical call.

CAPN1 p.Arg481Gln

c.1442G>A · rs763471308 · VCV584446

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9942 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive spastic paraplegia type 76

Computational evidence

Protein change
AlphaMissense	0.9942	likely pathogenic
REVEL	0.911	moderately pathogenic-leaning
SaProt	LLR -11.70	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 29 kb · p 4.3e-06 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,940 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00031% 5/1,613,338 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,470
South Asian	0.0011%	91,092
European (non-Finnish)	0.00017%	589,946

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.Arg481Gln
Coding: c.1442G>A
MANE Select: NM_005186
dbSNP: rs763471308
Type: single nucleotide variant
Location: chr11:65206551 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 481: 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

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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-arg481gln (accessed [today's date]).

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