Is CAPN3 p.Ser559Pro (c.1675T>C) pathogenic?

CAPN3 p.Ser559Pro (c.1675T>C) is classified Uncertain significance in CAPN3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-03-27). AlphaMissense: likely pathogenic (0.9991); Absent from gnomAD v4.1.

How common is CAPN3 p.Ser559Pro (c.1675T>C) in the general population?

CAPN3 p.Ser559Pro (c.1675T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CAPN3 p.Ser559Pro (c.1675T>C)?

AlphaMissense predicts likely pathogenic (score 0.9991) — an in-silico prediction, not a clinical call.

CAPN3 p.Ser559Pro

c.1675T>C · rs1595838688 · VCV807218

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9991 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9991	likely pathogenic · top 1% in CAPN3
REVEL	0.947	strongly pathogenic-leaning
SaProt	LLR -15.70	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 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CAPN3
Protein: p.Ser559Pro
Coding: c.1675T>C
MANE Select: NM_000070
dbSNP: rs1595838688
Type: single nucleotide variant
Location: chr15:42402932 (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 559: the 'domain iii' region

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

Similar variants

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CAPN3 c.1194-9A>G Pathogenic ★★★ same type
CAPN3 c.1746-20C>G Pathogenic ★★★ same type
CAPN3 c.1993-1G>A Pathogenic ★★★ same type
CAPN3 c.499-1G>A Pathogenic ★★★ same type
CAPN3 p.Ala702Val Pathogenic ★★★ same type
CAPN3 p.Ala798Glu Pathogenic ★★★ ⚠ 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/capn3-p-ser559pro (accessed [today's date]).

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