Is CAPN5 p.Glu561Lys (c.1681G>A) pathogenic?

CAPN5 p.Glu561Lys (c.1681G>A) is classified Uncertain significance in CAPN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-23). AlphaMissense: likely benign (0.0761); Very rare (popmax 0.00549%, sas).

How common is CAPN5 p.Glu561Lys (c.1681G>A) in the general population?

CAPN5 p.Glu561Lys (c.1681G>A) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about CAPN5 p.Glu561Lys (c.1681G>A)?

AlphaMissense predicts likely benign (score 0.0761) — an in-silico prediction, not a clinical call.

CAPN5 p.Glu561Lys

c.1681G>A · rs782296700 · VCV1376460

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0761 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0761	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -6.99	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 2.9	GERP -3.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 39 kb · p 0.00098 · regional, not allelic
Overall
CADD	10.36	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 0.00549% South Asian · 5/91,038 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000621% 10/1,611,566 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,208
Remaining individualsnot grpmax-eligible	0.00481%	20,769
Admixed American	0.00167%	59,884
European (non-Finnish)	8.48e-05%	1,178,657

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: CAPN5
Protein: p.Glu561Lys
Coding: c.1681G>A
MANE Select: NM_004055
dbSNP: rs782296700
Type: single nucleotide variant
Location: chr11:77122653 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.71 · 1 PDB
Residue 561: the c2 domain

Full CAPN5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN5 p.Glu561= Likely benign ★★ same residue
CAPN5 p.Arg243Leu Pathogenic ★★ ⚠ same type
CAPN5 p.Arg289Trp Pathogenic ★★ ⚠ same type
CAPN5 p.Ala118Val Uncertain significance ★★ ⚠ same type
CAPN5 p.Ala183Ser Uncertain significance ★★ ⚠ same type
CAPN5 p.Ala185Val Uncertain significance ★★ ⚠ same type
CAPN5 p.Ala237Val Uncertain significance ★★ ⚠ same type
CAPN5 p.Ala245Val 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/capn5-p-glu561lys (accessed [today's date]).

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