Is CAPN1 p.Ser539Ala (c.1615T>G) pathogenic?

CAPN1 p.Ser539Ala (c.1615T>G) is classified Uncertain significance in CAPN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: likely benign (0.0815); Very rare (popmax 0.00519%, amr); Associated with Inborn genetic diseases.

What condition is associated with CAPN1 p.Ser539Ala (c.1615T>G)?

CAPN1 p.Ser539Ala (c.1615T>G) is associated with Inborn genetic diseases (ClinVar).

How common is CAPN1 p.Ser539Ala (c.1615T>G) in the general population?

CAPN1 p.Ser539Ala (c.1615T>G) is very rare (popmax 0.00519%, amr) (gnomAD).

What do computational predictors say about CAPN1 p.Ser539Ala (c.1615T>G)?

AlphaMissense predicts likely benign (score 0.0815) — an in-silico prediction, not a clinical call.

CAPN1 p.Ser539Ala

c.1615T>G · VCV4605180

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0815 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00519%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0815	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -7.95	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 6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 29 kb · p 4.3e-06 · regional, not allelic
Overall
CADD	22.3	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 0.00519% Admixed American · 3/57,754 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000682%

Overall 0.000207% 3/1,446,318 alleles · very 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: CAPN1
Protein: p.Ser539Ala
Coding: c.1615T>G
MANE Select: NM_005186
Type: single nucleotide variant
Location: chr11:65208064 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 539: the 'linker' region

Full CAPN1 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

CAPN1 p.Arg104His Uncertain significance ★★ ⚠ same condition
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CAPN1 p.Arg293Trp Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg347Cys Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg347His Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg48Gln Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg581Gln Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg599His 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/capn1-p-ser539ala (accessed [today's date]).

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