Is CDK5RAP2 p.Ala696Val (c.2087C>T) pathogenic?

CDK5RAP2 p.Ala696Val (c.2087C>T) is classified Uncertain significance in CDK5RAP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-20). AlphaMissense: likely benign (0.0951); Ultra-rare (popmax 0.0367%, amr); Associated with microcephaly 3, primary, autosomal recessive.

What condition is associated with CDK5RAP2 p.Ala696Val (c.2087C>T)?

CDK5RAP2 p.Ala696Val (c.2087C>T) is associated with microcephaly 3, primary, autosomal recessive (ClinVar).

How common is CDK5RAP2 p.Ala696Val (c.2087C>T) in the general population?

CDK5RAP2 p.Ala696Val (c.2087C>T) is ultra-rare (popmax 0.0367%, amr) (gnomAD).

What do computational predictors say about CDK5RAP2 p.Ala696Val (c.2087C>T)?

AlphaMissense predicts likely benign (score 0.0951) — an in-silico prediction, not a clinical call.

CDK5RAP2 p.Ala696Val

c.2087C>T · rs369208545 · VCV364768

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0951 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly 3, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.0951	likely benign
REVEL	0.021	moderately benign-leaning
SaProt	LLR -6.03	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 0.025	GERP -4.3
Regional constraint	o/e 0.98	unconstrained · MANE · 191 kb · p 0.44 · regional, not allelic
Overall
CADD	3.357	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 0.0367% Admixed American · 22/60,022 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.00341% 55/1,614,060 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0367%	2,728
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0048%	20,834
East Asian	0.00446%	22,440
African / African-American	0.004%	25,007
European (non-Finnish)	0.00195%	51,303
South Asian	0.0011%	91,078

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.Ala696Val
Coding: c.2087C>T
MANE Select: NM_018249
dbSNP: rs369208545
Type: single nucleotide variant
Location: chr9:120467879 (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 p.Ala696Pro Uncertain significance ★ ⚠ same residue
CDK5RAP2 p.Ala696= Likely benign ★ same residue
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

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-ala696val (accessed [today's date]).

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