Is CDK5RAP2 p.Arg427Gln (c.1280G>A) pathogenic?

CDK5RAP2 p.Arg427Gln (c.1280G>A) is classified Conflicting classifications of pathogenicity in CDK5RAP2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2023-02-06). AlphaMissense: likely benign (0.0738); Ultra-rare (popmax 0.0846%, sas); Associated with intellectual disability.

What condition is associated with CDK5RAP2 p.Arg427Gln (c.1280G>A)?

CDK5RAP2 p.Arg427Gln (c.1280G>A) is associated with intellectual disability (ClinVar).

How common is CDK5RAP2 p.Arg427Gln (c.1280G>A) in the general population?

CDK5RAP2 p.Arg427Gln (c.1280G>A) is ultra-rare (popmax 0.0846%, sas) (gnomAD).

What do computational predictors say about CDK5RAP2 p.Arg427Gln (c.1280G>A)?

AlphaMissense predicts likely benign (score 0.0738) — an in-silico prediction, not a clinical call.

CDK5RAP2 p.Arg427Gln

c.1280G>A · rs141387242 · VCV1307591

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0738 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0846%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.0738	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -6.27	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 -3.5	GERP -5.4
Regional constraint	o/e 0.98	unconstrained · MANE · 191 kb · p 0.44 · regional, not allelic
Overall
CADD	17.52	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 0.0846% South Asian · 77/91,018 alleles

Filtering AF 0.0694% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0637%

Overall 0.00812% 131/1,613,868 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0846%	1,182
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
Remaining individualsnot grpmax-eligible	0.0096%	10,415
Finnishnot grpmax-eligible	0.00937%	10,669
African / African-American	0.004%	24,991
European (non-Finnish)	0.00297%	33,714
Admixed American	0.00167%	59,998

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.Arg427Gln
Coding: c.1280G>A
MANE Select: NM_018249
dbSNP: rs141387242
Type: single nucleotide variant
Location: chr9:120518458 (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

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDK5RAP2 p.Arg427Ter Pathogenic ★★ same residue
CDK5RAP2 p.Ala762Thr Uncertain significance ★ ⚠ same condition
CDK5RAP2 p.Arg260Gln Conflicting classifications of pathogenicity ★ ⚠ same condition
CDK5RAP2 p.Asn497Ser Conflicting classifications of pathogenicity ★ ⚠ same condition
CDK5RAP2 c.5308-4G>C Likely benign same condition
CDK5RAP2 p.Glu243Lys Likely benign ⚠ same condition
CDK5RAP2 p.Glu49Lys Likely benign same condition
CDK5RAP2 p.Ser1782Asn Likely benign ⚠ 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-arg427gln (accessed [today's date]).

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