Is CDK8 p.Val345Ile (c.1033G>A) pathogenic?

CDK8 p.Val345Ile (c.1033G>A) is classified Uncertain significance in CDK8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-24). AlphaMissense: likely benign (0.3244); Very rare (popmax 0.00144%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CDK8 p.Val345Ile (c.1033G>A)?

CDK8 p.Val345Ile (c.1033G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CDK8 p.Val345Ile (c.1033G>A) in the general population?

CDK8 p.Val345Ile (c.1033G>A) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about CDK8 p.Val345Ile (c.1033G>A)?

AlphaMissense predicts likely benign (score 0.3244) — an in-silico prediction, not a clinical call.

CDK8 p.Val345Ile

c.1033G>A · VCV3489565

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3244 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3244	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -10.44	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 16 kb · p 1.1e-18 · regional, not allelic
Overall
CADD	28.6	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 0.00144% European (non-Finnish) · 17/1,179,230 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00123% 18/1,460,782 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00144%	69,366
South Asian	0.0011%	91,016

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.Val345Ile
Coding: c.1033G>A
MANE Select: NM_001260
Type: single nucleotide variant
Location: chr13:26401270 (GRCh38)
Gene constraint: LOEUF 0.646 · pLI 0.47 (gnomAD)
Structure: AlphaFold pLDDT 80.75 · 36 PDB
Residue 345: a turn

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.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
CDK8 p.Gln440His 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-val345ile (accessed [today's date]).

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