Is CDK5RAP2 p.Gln175fs (c.524_528del) pathogenic?

CDK5RAP2 p.Gln175fs (c.524528del) is classified Pathogenic/Likely pathogenic in CDK5RAP2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-02-26). Ultra-rare (popmax 0.0123%, nfe); Associated with CDK5RAP2-related disorder.

What condition is associated with CDK5RAP2 p.Gln175fs (c.524_528del)?

CDK5RAP2 p.Gln175fs (c.524_528del) is associated with CDK5RAP2-related disorder, microcephaly 3, primary, autosomal recessive (ClinVar).

How common is CDK5RAP2 p.Gln175fs (c.524_528del) in the general population?

CDK5RAP2 p.Gln175fs (c.524_528del) is ultra-rare (popmax 0.0123%, nfe) (gnomAD).

CDK5RAP2 p.Gln175fs

c.524_528del · rs587783393 · VCV127196

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, nfe)

Conditions

CDK5RAP2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 38
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 1.1, phastCons 1
Overall
CADD	34.0	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 0.0123% European (non-Finnish) · 145/1,180,002 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00997%

Overall 0.00942% 152/1,614,018 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0123%	8,138
Finnishnot grpmax-eligible	0.00469%	21,344
Remaining individualsnot grpmax-eligible	0.0032%	31,241
African / African-American	0.00267%	37,466

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.Gln175fs
Coding: c.524_528del
MANE Select: NM_018249
dbSNP: rs587783393
Type: Deletion
Location: chr9:120536506 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.11 · 5 PDB
Residue 175: the 'interaction with nckap5l' region

Full CDK5RAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CDK5RAP2-related disorder

Also linked: microcephaly 3, primary, autosomal recessive

Similar variants

CDK5RAP2 p.Leu1718fs Likely pathogenic ★★ same condition
CDK5RAP2 p.Met1326fs Likely pathogenic ★★ same condition
CDK5RAP2 p.Val1033fs Pathogenic ★★ same condition
CDK5RAP2 p.Asn459fs Pathogenic ★ same condition
CDK5RAP2 p.Glu275fs Likely pathogenic ★ same condition
CDK5RAP2 p.Glu340fs Pathogenic ★ same condition
CDK5RAP2 p.His1264fs Likely pathogenic ★ same condition
CDK5RAP2 p.Ile67fs 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-gln175fs (accessed [today's date]).

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