Is CDK5RAP2 p.Asp758= (c.2274T>C) pathogenic?

CDK5RAP2 p.Asp758= (c.2274T>C) is classified Benign/Likely benign in CDK5RAP2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 35.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with microcephaly 3, primary, autosomal recessive.

What condition is associated with CDK5RAP2 p.Asp758= (c.2274T>C)?

CDK5RAP2 p.Asp758= (c.2274T>C) is associated with microcephaly 3, primary, autosomal recessive (ClinVar).

CDK5RAP2 p.Asp758=

Q: How common is CDK5RAP2 p.Asp758= (c.2274T>C) in the general population?

CDK5RAP2 p.Asp758= (c.2274T>C) is common (popmax 35.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2274T>C · rs2501727 · VCV136705

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 35.7%, afr) — 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 carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -4, phastCons 0.42
Overall
CADD	0.896	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 35.7% African / African-American · 26,737/74,956 alleles

Filtering AF 35.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 35.2%

Overall 12.2% 197,194/1,613,736 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	35.7%	3
East Asian	35.1%	3
Amishnot grpmax-eligible	17.1%	6
Admixed American	15.7%	6
South Asian	13.7%	7
Remaining individualsnot grpmax-eligible	13.7%	7
Middle Eastern	13.4%	7
Finnishnot grpmax-eligible	11.1%	9
European (non-Finnish)	9.64%	10
Ashkenazi Jewishnot grpmax-eligible	8.39%	12

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.Asp758=
Coding: c.2274T>C
MANE Select: NM_018249
dbSNP: rs2501727
Type: single nucleotide variant
Location: chr9:120458551 (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 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
CDK5RAP2 p.Glu1516Ter 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-asp758 (accessed [today's date]).

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