Is CAPN8 p.Ser56Pro (c.166T>C) pathogenic?

CAPN8 p.Ser56Pro (c.166T>C) is classified Uncertain significance in CAPN8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-20). AlphaMissense: likely benign (0.0915); Ultra-rare (popmax 0.0329%, afr).

How common is CAPN8 p.Ser56Pro (c.166T>C) in the general population?

CAPN8 p.Ser56Pro (c.166T>C) is ultra-rare (popmax 0.0329%, afr) (gnomAD).

What do computational predictors say about CAPN8 p.Ser56Pro (c.166T>C)?

AlphaMissense predicts likely benign (score 0.0915) — an in-silico prediction, not a clinical call.

CAPN8 p.Ser56Pro

c.166T>C · VCV3484859

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0915 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0915	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -9.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 124 kb · p 0.038 · regional, not allelic
Overall
CADD	22.5	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 0.0329% African / African-American · 24/73,006 alleles

Filtering AF 0.0227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0192%

Overall 0.00232% 36/1,551,796 alleles · ultra-rare exomes 16/1,399,692 · genomes 20/152,104 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0329%	3,042
Remaining individualsnot grpmax-eligible	0.00997%	10,030
Admixed American	0.00981%	10,196
European (non-Finnish)	8.72e-05%	1,147,044

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.Ser56Pro
Coding: c.166T>C
MANE Select: NM_001143962
Type: single nucleotide variant
Location: chr1:223665481 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.15 · 1 PDB
Residue 56: 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.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
CAPN8 p.Ala248Ser 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-ser56pro (accessed [today's date]).

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