Is CDK5RAP2 p.Asn459fs (c.1376del) pathogenic?

CDK5RAP2 p.Asn459fs (c.1376del) is classified Pathogenic in CDK5RAP2 (ClinVar, Single submitter, 1 submitter). Very rare (popmax 8.48e-05%, nfe); Associated with microcephaly 3, primary, autosomal recessive.

What condition is associated with CDK5RAP2 p.Asn459fs (c.1376del)?

CDK5RAP2 p.Asn459fs (c.1376del) is associated with microcephaly 3, primary, autosomal recessive (ClinVar).

How common is CDK5RAP2 p.Asn459fs (c.1376del) in the general population?

CDK5RAP2 p.Asn459fs (c.1376del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

CDK5RAP2 p.Asn459fs

c.1376del · rs1588472215 · VCV694012

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

microcephaly 3, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 13 of 38
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.017	GERP -4.6, phastCons 0.006

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,178,976 alleles

Overall 6.85e-05% 1/1,460,108 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: CDK5RAP2
Protein: p.Asn459fs
Coding: c.1376del
MANE Select: NM_018249
dbSNP: rs1588472215
Type: Deletion
Location: chr9:120491413 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.11 · 5 PDB

Full CDK5RAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly 3, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDK5RAP2 p.Gln175fs Pathogenic/Likely pathogenic ★★ same condition
CDK5RAP2 p.Leu1718fs Likely pathogenic ★★ same condition
CDK5RAP2 p.Met1326fs Likely pathogenic ★★ same condition
CDK5RAP2 p.Val1033fs Pathogenic ★★ same condition
CDK5RAP2 p.Glu340fs Pathogenic ★ same condition
CDK5RAP2 p.His1264fs Likely pathogenic ★ same condition
CDK5RAP2 p.Ile67fs Pathogenic ★ same condition
CDK5RAP2 p.Leu1006fs Likely pathogenic ★ 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/cdk5rap2-p-asn459fs (accessed [today's date]).

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