Is CDK5RAP2 p.Leu557fs (c.1668_1674del) pathogenic?

CDK5RAP2 p.Leu557fs (c.16681674del) is classified Pathogenic in CDK5RAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-05). Very rare (popmax 0.00169%, nfe).

How common is CDK5RAP2 p.Leu557fs (c.1668_1674del) in the general population?

CDK5RAP2 p.Leu557fs (c.1668_1674del) is very rare (popmax 0.00169%, nfe) (gnomAD).

CDK5RAP2 p.Leu557fs

c.1668_1674del · rs775170271 · VCV2188880

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

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 15 of 38
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.2	GERP 0.31, phastCons 1
Overall
CADD	33.0	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) · 20/1,180,006 alleles

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

Overall 0.00124% 20/1,613,954 alleles · very rare

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.Leu557fs
Coding: c.1668_1674del
MANE Select: NM_018249
dbSNP: rs775170271
Type: Deletion
Location: chr9:120477403 (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

Similar variants

CDK5RAP2 p.Gln175fs Pathogenic/Likely pathogenic ★★ same type
CDK5RAP2 p.Leu1718fs Likely pathogenic ★★ same type
CDK5RAP2 p.Met1326fs Likely pathogenic ★★ same type
CDK5RAP2 p.Val1033fs Pathogenic ★★ same type
CDK5RAP2 c.2107-15_2108del Likely pathogenic ★ same type
CDK5RAP2 c.4408_4414+15del Likely pathogenic ★ same type
CDK5RAP2 p.Asn1388fs Pathogenic ★ same type
CDK5RAP2 p.Asn459fs Pathogenic ★ same type

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-leu557fs (accessed [today's date]).

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