Is CAPN5 p.Lys445Glu (c.1333A>G) pathogenic?

CAPN5 p.Lys445Glu (c.1333A>G) is classified Conflicting classifications of pathogenicity in CAPN5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-13). AlphaMissense: ambiguous (0.3684); Rare (popmax 0.274%, eas); Associated with Inborn genetic diseases.

What condition is associated with CAPN5 p.Lys445Glu (c.1333A>G)?

CAPN5 p.Lys445Glu (c.1333A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CAPN5 p.Lys445Glu (c.1333A>G) in the general population?

CAPN5 p.Lys445Glu (c.1333A>G) is rare (popmax 0.274%, eas) (gnomAD).

What do computational predictors say about CAPN5 p.Lys445Glu (c.1333A>G)?

AlphaMissense predicts ambiguous (score 0.3684) — an in-silico prediction, not a clinical call.

CAPN5 p.Lys445Glu

c.1333A>G · rs199893083 · VCV1092533

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3684 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.274%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3684	ambiguous
REVEL	0.158	moderately benign-leaning
SaProt	LLR -10.88	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.15	GERP -2
Regional constraint	o/e 0.89	unconstrained · MANE · 39 kb · p 0.00098 · regional, not allelic
Overall
CADD	16.56	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 0.274% East Asian · 123/44,890 alleles

Filtering AF 0.235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.22%

Overall 0.00917% 148/1,613,748 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.274%	365
Remaining individualsnot grpmax-eligible	0.024%	4,167
Middle Eastern	0.0165%	6,062
South Asian	0.00769%	13,006
European (non-Finnish)	0.00017%	589,957

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.Lys445Glu
Coding: c.1333A>G
MANE Select: NM_004055
dbSNP: rs199893083
Type: single nucleotide variant
Location: chr11:77120755 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.71 · 1 PDB
Residue 445: the 'domain iii' region

Full CAPN5 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

CAPN5 p.Ala183Ser Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala237Val Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala253Thr Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala34Val Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala357Val Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala362Gly Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala447Thr Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala552Ser 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/capn5-p-lys445glu (accessed [today's date]).

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