Is CDK5RAP2 p.Pro1002Ala (c.3004C>G) pathogenic?

CDK5RAP2 p.Pro1002Ala (c.3004C>G) is classified Uncertain significance in CDK5RAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-20). AlphaMissense: likely benign (0.0641); Very rare (popmax 0.00195%, nfe).

How common is CDK5RAP2 p.Pro1002Ala (c.3004C>G) in the general population?

CDK5RAP2 p.Pro1002Ala (c.3004C>G) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about CDK5RAP2 p.Pro1002Ala (c.3004C>G)?

AlphaMissense predicts likely benign (score 0.0641) — an in-silico prediction, not a clinical call.

CDK5RAP2 p.Pro1002Ala

c.3004C>G · rs370366333 · VCV2143598

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0641 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0641	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -6.08	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 4.5	GERP 0.14, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 191 kb · p 0.44 · regional, not allelic
Overall
CADD	10.86	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00195% European (non-Finnish) · 23/1,179,898 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00155% 25/1,613,888 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,300
Admixed American	0.00167%	60,004
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Pro1002Ala
Coding: c.3004C>G
MANE Select: NM_018249
dbSNP: rs370366333
Type: single nucleotide variant
Location: chr9:120447916 (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 1002: the 'interaction with mapre1' region

Full CDK5RAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDK5RAP2 p.Pro1002= Likely benign ★★ same residue
CDK5RAP2 c.4005-1G>A Pathogenic ★★ same type
CDK5RAP2 c.4963+1G>A Likely pathogenic ★★ same type
CDK5RAP2 p.Arg1403Ter Pathogenic/Likely pathogenic ★★ same type
CDK5RAP2 p.Arg1481Ter Pathogenic/Likely pathogenic ★★ same type
CDK5RAP2 p.Arg1558Ter Pathogenic ★★ same type
CDK5RAP2 p.Arg427Ter Pathogenic ★★ same type
CDK5RAP2 p.Gln1301Ter Pathogenic/Likely pathogenic ★★ same type

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-pro1002ala (accessed [today's date]).

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