Is CDK5RAP2 p.Ala1577Val (c.4730C>T) pathogenic?

CDK5RAP2 p.Ala1577Val (c.4730C>T) is classified Conflicting classifications of pathogenicity in CDK5RAP2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-09-01). AlphaMissense: likely benign (0.1158); Rare (popmax 0.155%, nfe); Associated with microcephaly 3, primary, autosomal recessive.

What condition is associated with CDK5RAP2 p.Ala1577Val (c.4730C>T)?

CDK5RAP2 p.Ala1577Val (c.4730C>T) is associated with microcephaly 3, primary, autosomal recessive (ClinVar).

How common is CDK5RAP2 p.Ala1577Val (c.4730C>T) in the general population?

CDK5RAP2 p.Ala1577Val (c.4730C>T) is rare (popmax 0.155%, nfe) (gnomAD).

What do computational predictors say about CDK5RAP2 p.Ala1577Val (c.4730C>T)?

AlphaMissense predicts likely benign (score 0.1158) — an in-silico prediction, not a clinical call.

CDK5RAP2 p.Ala1577Val

c.4730C>T · rs143946953 · VCV210638

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1158 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.155%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly 3, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.1158	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -6.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.079	GERP -1.2
Regional constraint	o/e 0.98	unconstrained · MANE · 191 kb · p 0.44 · regional, not allelic
Overall
CADD	17.85	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.155% European (non-Finnish) · 1,830/1,177,664 alleles

Filtering AF 0.149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.147%

Overall 0.12% 1,929/1,609,356 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.155%	644
Remaining individualsnot grpmax-eligible	0.0785%	1,274
Ashkenazi Jewishnot grpmax-eligible	0.0405%	2,466
Finnishnot grpmax-eligible	0.0259%	3,864
African / African-American	0.02%	4,999
Admixed American	0.01%	10,002
East Asian	0.00223%	44,872

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.Ala1577Val
Coding: c.4730C>T
MANE Select: NM_018249
dbSNP: rs143946953
Type: single nucleotide variant
Location: chr9:120407245 (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 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
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-ala1577val (accessed [today's date]).

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