Is CDK5RAP2 p.Arg221= (c.663A>G) pathogenic?

CDK5RAP2 p.Arg221= (c.663A>G) is classified Likely benign in CDK5RAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-26). Ultra-rare (popmax 0.0934%, sas); Associated with Inborn genetic diseases.

What condition is associated with CDK5RAP2 p.Arg221= (c.663A>G)?

CDK5RAP2 p.Arg221= (c.663A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CDK5RAP2 p.Arg221= (c.663A>G) in the general population?

CDK5RAP2 p.Arg221= (c.663A>G) is ultra-rare (popmax 0.0934%, sas) (gnomAD).

CDK5RAP2 p.Arg221=

c.663A>G · rs780643069 · VCV2606406

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0934%, sas)

Conditions

Inborn genetic diseases

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 0.91	GERP -2.9, phastCons 1
Overall
CADD	13.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0934% South Asian · 85/91,020 alleles

Filtering AF 0.0773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0714%

Overall 0.00534% 86/1,611,680 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0934%	1,071
Remaining individualsnot grpmax-eligible	0.0016%	62,416

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.Arg221=
Coding: c.663A>G
MANE Select: NM_018249
dbSNP: rs780643069
Type: single nucleotide variant
Location: chr9:120530140 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDK5RAP2 c.1727+6C>G Uncertain significance ★★ same condition
CDK5RAP2 p.Ala181Ser Uncertain significance ★★ ⚠ same condition
CDK5RAP2 p.Ala235Thr Uncertain significance ★★ ⚠ same condition
CDK5RAP2 p.Ala326Ser Uncertain significance ★★ ⚠ same condition
CDK5RAP2 p.Ala358Thr Uncertain significance ★★ ⚠ same condition
CDK5RAP2 p.Ala382Val Uncertain significance ★★ ⚠ same condition
CDK5RAP2 p.Ala764Pro Uncertain significance ★★ ⚠ same condition
CDK5RAP2 p.Ala905Val Uncertain significance ★★ ⚠ 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-arg221 (accessed [today's date]).

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