Is CAPN8 p.Arg310Trp (c.928C>T) pathogenic?

CAPN8 p.Arg310Trp (c.928C>T) is classified Uncertain significance in CAPN8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-07). AlphaMissense: likely benign (0.094); Ultra-rare (popmax 0.0342%, afr).

How common is CAPN8 p.Arg310Trp (c.928C>T) in the general population?

CAPN8 p.Arg310Trp (c.928C>T) is ultra-rare (popmax 0.0342%, afr) (gnomAD).

What do computational predictors say about CAPN8 p.Arg310Trp (c.928C>T)?

AlphaMissense predicts likely benign (score 0.094) — an in-silico prediction, not a clinical call.

CAPN8 p.Arg310Trp

c.928C>T · rs150136459 · VCV2458067

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.094 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0342%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.094	likely benign
REVEL	0.357	indeterminate
SaProt	LLR -8.75	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.5	GERP -4.6
Regional constraint	o/e 1.08	unconstrained · MANE · 124 kb · p 0.038 · regional, not allelic
Overall
CADD	18.12	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0342% African / African-American · 25/73,120 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0202%

Overall 0.00213% 33/1,551,482 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0342%	2,925
East Asian	0.00244%	40,914
Admixed American	0.00196%	50,990
Remaining individualsnot grpmax-eligible	0.00166%	60,110
European (non-Finnish)	0.000436%	229,379

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.Arg310Trp
Coding: c.928C>T
MANE Select: NM_001143962
dbSNP: rs150136459
Type: single nucleotide variant
Location: chr1:223620238 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.15 · 1 PDB
Residue 310: the calpain catalytic domain; an α-helix

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

Similar variants

CAPN8 p.Arg310Gln Likely benign ★ 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-arg310trp (accessed [today's date]).

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