Is CAPN3 p.Ala34Pro (c.100G>C) pathogenic?

CAPN3 p.Ala34Pro (c.100G>C) is classified Uncertain significance in CAPN3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-02). AlphaMissense: likely benign (0.09); Rare (popmax 0.147%, eas); Associated with Inborn genetic diseases.

What condition is associated with CAPN3 p.Ala34Pro (c.100G>C)?

CAPN3 p.Ala34Pro (c.100G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CAPN3 p.Ala34Pro (c.100G>C) in the general population?

CAPN3 p.Ala34Pro (c.100G>C) is rare (popmax 0.147%, eas) (gnomAD).

What do computational predictors say about CAPN3 p.Ala34Pro (c.100G>C)?

AlphaMissense predicts likely benign (score 0.09) — an in-silico prediction, not a clinical call.

CAPN3 p.Ala34Pro

c.100G>C · rs772534302 · VCV2439724

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.09 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.147%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.09	likely benign
REVEL	0.235	benign-leaning
SaProt	LLR -6.23	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 3.8	GERP -0.25, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	20.2	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 0.147% East Asian · 66/44,888 alleles

Filtering AF 0.119% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.108%

Overall 0.00451% 66/1,461,878 alleles · rare

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: CAPN3
Protein: p.Ala34Pro
Coding: c.100G>C
MANE Select: NM_000070
dbSNP: rs772534302
Type: single nucleotide variant
Location: chr15:42359905 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.18 · 5 PDB
Residue 34: the 'disordered' region

Full CAPN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CAPN3 p.Ala34Gly Uncertain significance ★ ⚠ same residue
CAPN3 p.Ala34Thr Uncertain significance ★ ⚠ same residue
CAPN3 p.Ala34fs Pathogenic ★★ same residue
CAPN3 p.Ala14Val Uncertain significance ★★ ⚠ same condition
CAPN3 p.Ala335Thr Uncertain significance ★★ ⚠ same condition
CAPN3 p.Ala385Val Uncertain significance ★★ ⚠ same condition
CAPN3 p.Ala750Val Uncertain significance ★★ ⚠ same condition
CAPN3 p.Arg386His Uncertain significance ★★ ⚠ 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/capn3-p-ala34pro (accessed [today's date]).

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