Is CDK5RAP2 p.Pro765Arg (c.2294C>G) pathogenic?

CDK5RAP2 p.Pro765Arg (c.2294C>G) is classified Benign/Likely benign in CDK5RAP2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-29). AlphaMissense: likely benign (0.1009); Low-frequency (popmax 1.17%, eas); Associated with microcephaly 3, primary, autosomal recessive.

What condition is associated with CDK5RAP2 p.Pro765Arg (c.2294C>G)?

CDK5RAP2 p.Pro765Arg (c.2294C>G) is associated with microcephaly 3, primary, autosomal recessive (ClinVar).

How common is CDK5RAP2 p.Pro765Arg (c.2294C>G) in the general population?

CDK5RAP2 p.Pro765Arg (c.2294C>G) is low-frequency (popmax 1.17%, eas) (gnomAD).

What do computational predictors say about CDK5RAP2 p.Pro765Arg (c.2294C>G)?

AlphaMissense predicts likely benign (score 0.1009) — an in-silico prediction, not a clinical call.

CDK5RAP2 p.Pro765Arg

c.2294C>G · rs139706626 · VCV158134

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1009 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.17%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly 3, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.1009	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -6.43	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 4.2	GERP -1.3, phastCons 0.93
Regional constraint	o/e 0.98	unconstrained · MANE · 191 kb · p 0.44 · regional, not allelic
Overall
CADD	14.45	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 1.17% East Asian · 527/44,878 alleles

Filtering AF 1.09% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.06%

Overall 0.0477% 770/1,614,164 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.17%	85
Remaining individualsnot grpmax-eligible	0.163%	613
South Asian	0.117%	851
African / African-American	0.02%	5,003
Admixed American	0.00833%	12,005
European (non-Finnish)	0.00119%	84,286

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.Pro765Arg
Coding: c.2294C>G
MANE Select: NM_018249
dbSNP: rs139706626
Type: single nucleotide variant
Location: chr9:120458531 (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-pro765arg (accessed [today's date]).

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