Is CDK5RAP1 p.Arg339Cys (c.1015C>T) pathogenic?

CDK5RAP1 p.Arg339Cys (c.1015C>T) is classified Uncertain significance in CDK5RAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-19). AlphaMissense: likely benign (0.1898); Very rare (popmax 0.00891%, eas).

How common is CDK5RAP1 p.Arg339Cys (c.1015C>T) in the general population?

CDK5RAP1 p.Arg339Cys (c.1015C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about CDK5RAP1 p.Arg339Cys (c.1015C>T)?

AlphaMissense predicts likely benign (score 0.1898) — an in-silico prediction, not a clinical call.

CDK5RAP1 p.Arg339Cys

c.1015C>T · rs267605888 · VCV2556747

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1898 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1898	likely benign
REVEL	0.809	moderately pathogenic-leaning
SaProt	LLR -10.34	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 38 kb · p 0.004 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R353C vs ClinVar R339C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,894 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000558% 9/1,613,930 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,223
European (non-Finnish)	0.000424%	235,993

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: CDK5RAP1
Protein: p.Arg339Cys
Coding: c.1015C>T
MANE Select: NM_016408
dbSNP: rs267605888
Type: single nucleotide variant
Location: chr20:33379553 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.24
Residue 339: the radical sam core domain

Full CDK5RAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDK5RAP1 c.1107+5G>A Uncertain significance ★ same type
CDK5RAP1 p.Ala247Val Uncertain significance ★ ⚠ same type
CDK5RAP1 p.Ala51Thr Uncertain significance ★ ⚠ same type
CDK5RAP1 p.Arg130Gln Uncertain significance ★ ⚠ same type
CDK5RAP1 p.Arg169Gln Uncertain significance ★ ⚠ same type
CDK5RAP1 p.Arg169Trp Uncertain significance ★ ⚠ same type
CDK5RAP1 p.Arg171Cys Uncertain significance ★ ⚠ same type
CDK5RAP1 p.Arg177Lys Uncertain significance ★ ⚠ 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/cdk5rap1-p-arg339cys (accessed [today's date]).

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