Is CDK5RAP2 p.Ile1227Phe (c.3679A>T) pathogenic?

CDK5RAP2 p.Ile1227Phe (c.3679A>T) is classified Uncertain significance in CDK5RAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2014-04-08). AlphaMissense: likely benign (0.2541); Ultra-rare (popmax 0.0383%, amr); Associated with microcephaly 3, primary, autosomal recessive.

What condition is associated with CDK5RAP2 p.Ile1227Phe (c.3679A>T)?

CDK5RAP2 p.Ile1227Phe (c.3679A>T) is associated with microcephaly 3, primary, autosomal recessive (ClinVar).

How common is CDK5RAP2 p.Ile1227Phe (c.3679A>T) in the general population?

CDK5RAP2 p.Ile1227Phe (c.3679A>T) is ultra-rare (popmax 0.0383%, amr) (gnomAD).

What do computational predictors say about CDK5RAP2 p.Ile1227Phe (c.3679A>T)?

AlphaMissense predicts likely benign (score 0.2541) — an in-silico prediction, not a clinical call.

CDK5RAP2 p.Ile1227Phe

c.3679A>T · rs139203975 · VCV158143

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2541 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0383%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly 3, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.2541	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -8.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.53	donor gain · deltas
Pangolin	Δ0.27	gain · loss 0.11 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.43	GERP -0.94, phastCons 0.19
Regional constraint	o/e 0.98	unconstrained · MANE · 191 kb · p 0.44 · regional, not allelic
Overall
CADD	24.7	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 0.0383% Admixed American · 23/60,024 alleles

Filtering AF 0.0261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00514% 83/1,614,146 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0383%	2,610
African / African-American	0.0293%	3,410
Remaining individualsnot grpmax-eligible	0.0096%	10,418
European (non-Finnish)	0.00271%	36,875

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.Ile1227Phe
Coding: c.3679A>T
MANE Select: NM_018249
dbSNP: rs139203975
Type: single nucleotide variant
Location: chr9:120439442 (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 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
CDK5RAP2 p.Gln1743Ter Pathogenic ★★ same condition
CDK5RAP2 p.Glu1516Ter 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-ile1227phe (accessed [today's date]).

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