Is CDK5RAP2 p.Lys126Arg (c.377A>G) pathogenic?

CDK5RAP2 p.Lys126Arg (c.377A>G) is classified Uncertain significance in CDK5RAP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-01-23). AlphaMissense: likely benign (0.1185); Ultra-rare (popmax 0.0267%, eas); Associated with Inborn genetic diseases.

What condition is associated with CDK5RAP2 p.Lys126Arg (c.377A>G)?

CDK5RAP2 p.Lys126Arg (c.377A>G) is associated with Inborn genetic diseases, microcephaly 3, primary, autosomal recessive (ClinVar).

How common is CDK5RAP2 p.Lys126Arg (c.377A>G) in the general population?

CDK5RAP2 p.Lys126Arg (c.377A>G) is ultra-rare (popmax 0.0267%, eas) (gnomAD).

What do computational predictors say about CDK5RAP2 p.Lys126Arg (c.377A>G)?

AlphaMissense predicts likely benign (score 0.1185) — an in-silico prediction, not a clinical call.

CDK5RAP2 p.Lys126Arg

c.377A>G · rs567442825 · VCV2216514

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1185 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1185	likely benign
REVEL	0.154	moderately benign-leaning
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 191 kb · p 0.44 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% East Asian · 12/44,882 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00143% 23/1,613,476 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0267%	3,740
Remaining individualsnot grpmax-eligible	0.008%	12,496
South Asian	0.00659%	15,180

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.Lys126Arg
Coding: c.377A>G
MANE Select: NM_018249
dbSNP: rs567442825
Type: single nucleotide variant
Location: chr9:120545720 (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 126: the 'interaction with nckap5l' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: microcephaly 3, primary, autosomal recessive

Similar variants

CDK5RAP2 p.Lys126Gln 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-lys126arg (accessed [today's date]).

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