Is CAPN5 p.Glu28Lys (c.82G>A) pathogenic?

CAPN5 p.Glu28Lys (c.82G>A) is classified Conflicting classifications of pathogenicity in CAPN5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-06). AlphaMissense: likely benign (0.2415); Ultra-rare (popmax 0.0653%, afr).

How common is CAPN5 p.Glu28Lys (c.82G>A) in the general population?

CAPN5 p.Glu28Lys (c.82G>A) is ultra-rare (popmax 0.0653%, afr) (gnomAD).

What do computational predictors say about CAPN5 p.Glu28Lys (c.82G>A)?

AlphaMissense predicts likely benign (score 0.2415) — an in-silico prediction, not a clinical call.

CAPN5 p.Glu28Lys

c.82G>A · rs202150535 · VCV501412

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2415 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0653%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2415	likely benign
REVEL	0.338	indeterminate
SaProt	LLR -9.87	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 39 kb · p 0.00098 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0653% African / African-American · 49/75,062 alleles

Filtering AF 0.0506% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0455%

Overall 0.00477% 77/1,613,528 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0653%	1,532
Admixed American	0.025%	4,001
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0128%	7,812
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
South Asian	0.0011%	91,072
European (non-Finnish)	0.000169%	590,002

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.Glu28Lys
Coding: c.82G>A
MANE Select: NM_004055
dbSNP: rs202150535
Type: single nucleotide variant
Location: chr11:77084968 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.71 · 1 PDB
Residue 28: the calpain catalytic domain

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

Similar variants

OMP p.Arg28Cys Uncertain significance ★ ⚠ 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-glu28lys (accessed [today's date]).

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