Is CDK5RAP2 p.Leu1839= (c.5517G>A) pathogenic?

CDK5RAP2 p.Leu1839= (c.5517G>A) is classified Conflicting classifications of pathogenicity in CDK5RAP2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-24). Ultra-rare (popmax 0.0483%, amr); Associated with microcephaly 3, primary, autosomal recessive.

What condition is associated with CDK5RAP2 p.Leu1839= (c.5517G>A)?

CDK5RAP2 p.Leu1839= (c.5517G>A) is associated with microcephaly 3, primary, autosomal recessive (ClinVar).

How common is CDK5RAP2 p.Leu1839= (c.5517G>A) in the general population?

CDK5RAP2 p.Leu1839= (c.5517G>A) is ultra-rare (popmax 0.0483%, amr) (gnomAD).

CDK5RAP2 p.Leu1839=

c.5517G>A · rs374625129 · VCV788649

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0483%, amr)

Conditions

microcephaly 3, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.23	GERP 1.3, phastCons 0.23
Overall
CADD	8.592	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0483% Admixed American · 29/60,006 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.00607% 98/1,614,056 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0483%	2,069
European (non-Finnish)	0.00576%	17,353
African / African-American	0.00133%	74,930

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.Leu1839=
Coding: c.5517G>A
MANE Select: NM_018249
dbSNP: rs374625129
Type: single nucleotide variant
Location: chr9:120394573 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.11 · 5 PDB
Residue 1839: the 'interaction with pcnt and akap9' region

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.Leu1839Ser Uncertain significance ★ ⚠ same residue
CDK5RAP2 c.4005-1G>A Pathogenic ★★ same condition
CDK5RAP2 c.4963+1G>A Likely pathogenic ★★ same condition
CDK5RAP2 p.Arg1403Ter Pathogenic/Likely pathogenic ★★ same condition
CDK5RAP2 p.Arg1481Ter Pathogenic/Likely pathogenic ★★ same condition
CDK5RAP2 p.Arg1558Ter Pathogenic ★★ same condition
CDK5RAP2 p.Arg427Ter Pathogenic ★★ same condition
CDK5RAP2 p.Gln1743Ter 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-leu1839 (accessed [today's date]).

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