Is CDK5RAP2 p.Glu621Ala (c.1862A>C) pathogenic?

CDK5RAP2 p.Glu621Ala (c.1862A>C) is classified Uncertain significance in CDK5RAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-17). AlphaMissense: likely benign (0.1733); Very rare (popmax 0.000367%, nfe).

How common is CDK5RAP2 p.Glu621Ala (c.1862A>C) in the general population?

CDK5RAP2 p.Glu621Ala (c.1862A>C) is very rare (popmax 0.000367%, nfe) (gnomAD).

What do computational predictors say about CDK5RAP2 p.Glu621Ala (c.1862A>C)?

AlphaMissense predicts likely benign (score 0.1733) — an in-silico prediction, not a clinical call.

CDK5RAP2 p.Glu621Ala

c.1862A>C · rs1203143623 · VCV1960490

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1733 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000367%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1733	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -6.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	acceptor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 191 kb · p 0.44 · regional, not allelic
Overall
CADD	25.2	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 0.000367% European (non-Finnish) · 4/1,090,922 alleles

Filtering AF 8.6e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.8e-05%

Overall 0.000268% 4/1,494,952 alleles · very rare

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.Glu621Ala
Coding: c.1862A>C
MANE Select: NM_018249
dbSNP: rs1203143623
Type: single nucleotide variant
Location: chr9:120470217 (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

Similar variants

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
CDK5RAP2 p.Gln1474Ter 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-glu621ala (accessed [today's date]).

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