Is CAPN2 p.Ser586Leu (c.1757C>T) pathogenic?

CAPN2 p.Ser586Leu (c.1757C>T) is classified Uncertain significance in CAPN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: likely benign (0.1301); Ultra-rare (popmax 0.0165%, mid).

How common is CAPN2 p.Ser586Leu (c.1757C>T) in the general population?

CAPN2 p.Ser586Leu (c.1757C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CAPN2 p.Ser586Leu (c.1757C>T)?

AlphaMissense predicts likely benign (score 0.1301) — an in-silico prediction, not a clinical call.

CAPN2 p.Ser586Leu

c.1757C>T · rs533912773 · VCV2386097

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1301 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1301	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -6.55	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 0.37	GERP -2.4, phastCons 0.001
Regional constraint	o/e 0.88	unconstrained · MANE · 62 kb · p 0.00029 · regional, not allelic
Overall
CADD	22.1	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 0.0165% Middle Eastern · 1/6,052 alleles

Filtering AF 0.000741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000746% 12/1,607,720 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,052
East Asian	0.00447%	22,377
African / African-American	0.00267%	37,473
South Asian	0.00112%	89,446
European (non-Finnish)	0.00051%	196,134

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: CAPN2
Protein: p.Ser586Leu
Coding: c.1757C>T
MANE Select: NM_001748
dbSNP: rs533912773
Type: single nucleotide variant
Location: chr1:223769842 (GRCh38)
Gene constraint: LOEUF 1.026 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48 · 3 PDB
Residue 586: a β-strand; the ef-hand 1 domain; the 'domain iv' region

Full CAPN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN2 p.Ala248Thr Uncertain significance ★★ ⚠ same type
CAPN2 p.Gly72Asp Uncertain significance ★★ ⚠ same type
CAPN2 p.Asp48= Benign ★★ same type
CAPN2 p.Lys677Gln Benign ★★ ⚠ same type
CAPN2 p.Ala101Pro Uncertain significance ★ ⚠ same type
CAPN2 p.Ala171Asp Uncertain significance ★ ⚠ same type
CAPN2 p.Ala194Ser Uncertain significance ★ ⚠ same type
CAPN2 p.Ala247Pro 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/capn2-p-ser586leu (accessed [today's date]).

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