Is CAPN8 p.Arg77Gln (c.230G>A) pathogenic?

CAPN8 p.Arg77Gln (c.230G>A) is classified Uncertain significance in CAPN8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-01). AlphaMissense: ambiguous (0.4416); Ultra-rare (popmax 0.0314%, afr).

How common is CAPN8 p.Arg77Gln (c.230G>A) in the general population?

CAPN8 p.Arg77Gln (c.230G>A) is ultra-rare (popmax 0.0314%, afr) (gnomAD).

What do computational predictors say about CAPN8 p.Arg77Gln (c.230G>A)?

AlphaMissense predicts ambiguous (score 0.4416) — an in-silico prediction, not a clinical call.

CAPN8 p.Arg77Gln

c.230G>A · VCV3484858

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4416 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0314%, afr)

Computational evidence

Protein change
AlphaMissense	0.4416	ambiguous
REVEL	0.46	indeterminate
SaProt	LLR -9.95	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 2.1, phastCons 0.99
Regional constraint	o/e 1.08	unconstrained · MANE · 124 kb · p 0.038 · regional, not allelic
Overall
CADD	28.2	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

Grpmax group 0.0314% African / African-American · 23/73,132 alleles

Filtering AF 0.0215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.00503% 78/1,550,834 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0314%	3,180
Middle Eastern	0.0167%	5,990
Admixed American	0.00588%	16,999
Remaining individualsnot grpmax-eligible	0.00498%	20,070
European (non-Finnish)	0.00384%	26,045
Ashkenazi Jewishnot grpmax-eligible	0.00349%	28,628
East Asian	0.00245%	40,842
South Asian	0.00238%	42,011

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: CAPN8
Protein: p.Arg77Gln
Coding: c.230G>A
MANE Select: NM_001143962
Type: single nucleotide variant
Location: chr1:223665417 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.15 · 1 PDB
Residue 77: the calpain catalytic domain

Full CAPN8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN8 p.Arg77Trp Uncertain significance ★ same residue
CAPN8 p.Ala112Val Uncertain significance ★ ⚠ same type
CAPN8 p.Ala136Glu Uncertain significance ★ ⚠ same type
CAPN8 p.Ala136Thr Uncertain significance ★ ⚠ same type
CAPN8 p.Ala194Ser Uncertain significance ★ ⚠ same type
CAPN8 p.Ala231Ser Uncertain significance ★ ⚠ same type
CAPN8 p.Ala234Val Uncertain significance ★ ⚠ same type
CAPN8 p.Ala247Val Uncertain significance ★ ⚠ same type

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/capn8-p-arg77gln (accessed [today's date]).

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