Is CDK5RAP2 p.Leu1860= (c.5578T>C) pathogenic?

CDK5RAP2 p.Leu1860= (c.5578T>C) is classified Benign/Likely benign in CDK5RAP2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-18). Common (popmax 8.53%, eas) — too common for a highly-penetrant pathogenic allele; Associated with microcephaly 3, primary, autosomal recessive.

What condition is associated with CDK5RAP2 p.Leu1860= (c.5578T>C)?

CDK5RAP2 p.Leu1860= (c.5578T>C) is associated with microcephaly 3, primary, autosomal recessive (ClinVar).

CDK5RAP2 p.Leu1860=

Q: How common is CDK5RAP2 p.Leu1860= (c.5578T>C) in the general population?

CDK5RAP2 p.Leu1860= (c.5578T>C) is common (popmax 8.53%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.5578T>C · rs77100552 · VCV158167

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 8.53%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

microcephaly 3, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.35	donor gain · deltas
Constraint at this position
Conservation	phyloP 0.058	GERP -1.5
Overall
CADD	9.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.53% East Asian · 3,829/44,868 alleles

Filtering AF 8.31% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.22%

Overall 0.286% 4,612/1,614,160 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	8.53%	12
Ashkenazi Jewishnot grpmax-eligible	0.777%	129
Remaining individualsnot grpmax-eligible	0.51%	196
South Asian	0.166%	603
Admixed American	0.02%	5,002
Middle Eastern	0.0165%	6,062
African / African-American	0.0107%	9,381
European (non-Finnish)	0.00525%	19,033

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.Leu1860=
Coding: c.5578T>C
MANE Select: NM_018249
dbSNP: rs77100552
Type: single nucleotide variant
Location: chr9:120394512 (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 1860: 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.Leu1860Ter Likely pathogenic ★ 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-leu1860 (accessed [today's date]).

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