Is CDK5RAP2 p.Met1Val (c.1A>G) pathogenic?

CDK5RAP2 p.Met1Val (c.1A>G) is classified Uncertain significance in CDK5RAP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-25). Ultra-rare (popmax 0.0167%, amr).

How common is CDK5RAP2 p.Met1Val (c.1A>G) in the general population?

CDK5RAP2 p.Met1Val (c.1A>G) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

CDK5RAP2 p.Met1Val

c.1A>G · rs375556534 · VCV218752

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.048	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.5	GERP -4.4
Overall
CADD	0.234	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 0.0167% Admixed American · 10/59,966 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00682%

Overall 0.00305% 49/1,608,276 alleles · ultra-rare exomes 43/1,456,040 · genomes 6/152,236 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,997
Middle Eastern	0.0165%	6,078
Finnishnot grpmax-eligible	0.00782%	12,795
Remaining individualsnot grpmax-eligible	0.00482%	20,753
European (non-Finnish)	0.00238%	41,960
East Asian	0.00223%	44,858
African / African-American	0.00134%	74,850

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.Met1Val
Coding: c.1A>G
MANE Select: NM_018249
dbSNP: rs375556534
Type: single nucleotide variant
Location: chr9:120579978 (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 c.4005-1G>A Pathogenic ★★ same type
CDK5RAP2 c.4963+1G>A Likely pathogenic ★★ same type
CDK5RAP2 p.Arg1403Ter Pathogenic/Likely pathogenic ★★ same type
CDK5RAP2 p.Arg1481Ter Pathogenic/Likely pathogenic ★★ same type
CDK5RAP2 p.Arg1558Ter Pathogenic ★★ same type
CDK5RAP2 p.Arg427Ter Pathogenic ★★ same type
CDK5RAP2 p.Gln1301Ter Pathogenic/Likely pathogenic ★★ same type
CDK5RAP2 p.Gln1474Ter 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-met1val (accessed [today's date]).

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