Is CDK5RAP2 p.Arg1558Ter (c.4672C>T) pathogenic?

CDK5RAP2 p.Arg1558Ter (c.4672C>T) is classified Pathogenic in CDK5RAP2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-03-14). Very rare (popmax 0.00169%, nfe); Associated with microcephaly 3, primary, autosomal recessive.

What condition is associated with CDK5RAP2 p.Arg1558Ter (c.4672C>T)?

CDK5RAP2 p.Arg1558Ter (c.4672C>T) is associated with microcephaly 3, primary, autosomal recessive (ClinVar).

How common is CDK5RAP2 p.Arg1558Ter (c.4672C>T) in the general population?

CDK5RAP2 p.Arg1558Ter (c.4672C>T) is very rare (popmax 0.00169%, nfe) (gnomAD).

CDK5RAP2 p.Arg1558Ter

c.4672C>T · rs373278668 · VCV91407

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Conditions

microcephaly 3, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 31 of 38
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 1.3, phastCons 1
Overall
CADD	42.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00169% European (non-Finnish) · 20/1,180,028 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.0013% 21/1,614,010 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00169%	59,001
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.Arg1558Ter
Coding: c.4672C>T
MANE Select: NM_018249
dbSNP: rs373278668
Type: single nucleotide variant
Location: chr9:120408401 (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.Arg1558Gln Uncertain significance ★★ ⚠ 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.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-arg1558ter (accessed [today's date]).

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