Is CDK8 p.Pro333Leu (c.998C>T) pathogenic?

CDK8 p.Pro333Leu (c.998C>T) is classified Uncertain significance in CDK8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-27). AlphaMissense: likely benign (0.0938); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with CDK8 p.Pro333Leu (c.998C>T)?

CDK8 p.Pro333Leu (c.998C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CDK8 p.Pro333Leu (c.998C>T) in the general population?

CDK8 p.Pro333Leu (c.998C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CDK8 p.Pro333Leu (c.998C>T)?

AlphaMissense predicts likely benign (score 0.0938) — an in-silico prediction, not a clinical call.

CDK8 p.Pro333Leu

c.998C>T · rs765661340 · VCV3141608

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0938 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0938	likely benign
REVEL	0.406	indeterminate
SaProt	LLR -13.90	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 16 kb · p 1.1e-18 · regional, not allelic
Overall
CADD	25.4	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 0.0022% South Asian · 2/91,044 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000274% 4/1,460,760 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,522
European (non-Finnish)	0.00017%	589,522

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: CDK8
Protein: p.Pro333Leu
Coding: c.998C>T
MANE Select: NM_001260
dbSNP: rs765661340
Type: single nucleotide variant
Location: chr13:26400517 (GRCh38)
Gene constraint: LOEUF 0.646 · pLI 0.47 (gnomAD)
Structure: AlphaFold pLDDT 80.75 · 36 PDB
Residue 333: the protein kinase domain; an α-helix

Full CDK8 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

Similar variants

CDK8 p.Pro333Ser Uncertain significance ★ ⚠ same residue
CDK8 p.Met445Ile Uncertain significance ★★ ⚠ same condition
CDK8 p.Ala144Thr Uncertain significance ★ ⚠ same condition
CDK8 p.Arg356Gln Uncertain significance ★ ⚠ same condition
CDK8 p.Arg463Gln Uncertain significance ★ ⚠ same condition
CDK8 p.Asn245Asp Uncertain significance ★ ⚠ same condition
CDK8 p.Asn383Asp Uncertain significance ★ ⚠ same condition
CDK8 p.Asp42His Uncertain significance ★ ⚠ 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/cdk8-p-pro333leu (accessed [today's date]).

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