Is CDK5RAP2 p.Pro250Leu (c.749C>T) pathogenic?

CDK5RAP2 p.Pro250Leu (c.749C>T) is classified Conflicting classifications of pathogenicity in CDK5RAP2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-25). AlphaMissense: likely benign (0.0952); Rare (popmax 0.392%, sas); Associated with microcephaly 3, primary, autosomal recessive.

What condition is associated with CDK5RAP2 p.Pro250Leu (c.749C>T)?

CDK5RAP2 p.Pro250Leu (c.749C>T) is associated with microcephaly 3, primary, autosomal recessive (ClinVar).

How common is CDK5RAP2 p.Pro250Leu (c.749C>T) in the general population?

CDK5RAP2 p.Pro250Leu (c.749C>T) is rare (popmax 0.392%, sas) (gnomAD).

What do computational predictors say about CDK5RAP2 p.Pro250Leu (c.749C>T)?

AlphaMissense predicts likely benign (score 0.0952) — an in-silico prediction, not a clinical call.

CDK5RAP2 p.Pro250Leu

c.749C>T · rs568558844 · VCV158170

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0952 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.392%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly 3, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.0952	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -5.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.88, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 191 kb · p 0.44 · regional, not allelic
Overall
CADD	22.3	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 0.392% South Asian · 357/91,080 alleles

Filtering AF 0.358% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.345%

Overall 0.0233% 376/1,613,932 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.392%	255
Remaining individualsnot grpmax-eligible	0.0256%	3,906
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.00017%	589,922

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.Pro250Leu
Coding: c.749C>T
MANE Select: NM_018249
dbSNP: rs568558844
Type: single nucleotide variant
Location: chr9:120530054 (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-pro250leu (accessed [today's date]).

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