Is CDK5RAP2 p.Ala173= (c.519C>T) pathogenic?

CDK5RAP2 p.Ala173= (c.519C>T) is classified Conflicting classifications of pathogenicity in CDK5RAP2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-05-01). Ultra-rare (popmax 0.084%, afr); Associated with microcephaly 3, primary, autosomal recessive.

What condition is associated with CDK5RAP2 p.Ala173= (c.519C>T)?

CDK5RAP2 p.Ala173= (c.519C>T) is associated with microcephaly 3, primary, autosomal recessive (ClinVar).

How common is CDK5RAP2 p.Ala173= (c.519C>T) in the general population?

CDK5RAP2 p.Ala173= (c.519C>T) is ultra-rare (popmax 0.084%, afr) (gnomAD).

CDK5RAP2 p.Ala173=

c.519C>T · rs139736411 · VCV434649

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.084%, afr)

Conditions

microcephaly 3, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.14	GERP -1.9, phastCons 0.057
Overall
CADD	11.48	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.084% African / African-American · 63/75,020 alleles

Filtering AF 0.0674% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0613%

Overall 0.00892% 144/1,613,982 alleles · ultra-rare exomes 94/1,461,726 · genomes 50/152,256 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.084%	1,191
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0112%	8,928
Admixed American	0.00667%	15,001
South Asian	0.00549%	18,214
European (non-Finnish)	0.00542%	18,437

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.Ala173=
Coding: c.519C>T
MANE Select: NM_018249
dbSNP: rs139736411
Type: single nucleotide variant
Location: chr9:120536515 (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 173: the 'interaction with nckap5l' region

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.Ala173Val 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.Arg1558Ter Pathogenic ★★ same condition
CDK5RAP2 p.Arg427Ter Pathogenic ★★ same condition
CDK5RAP2 p.Gln1743Ter 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-ala173 (accessed [today's date]).

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