Is CDK8 p.Ala219Val (c.656C>T) pathogenic?

CDK8 p.Ala219Val (c.656C>T) is classified Uncertain significance in CDK8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-08). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1.

How common is CDK8 p.Ala219Val (c.656C>T) in the general population?

CDK8 p.Ala219Val (c.656C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDK8 p.Ala219Val (c.656C>T)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

CDK8 p.Ala219Val

c.656C>T · VCV3363909

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,588,460)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic
REVEL	0.721	pathogenic-leaning
SaProt	LLR -14.77	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.33	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 16 kb · p 1.1e-18 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

No allele count reported in gnomAD v4.1 (AN 1,588,460). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CDK8
Protein: p.Ala219Val
Coding: c.656C>T
MANE Select: NM_001260
Type: single nucleotide variant
Location: chr13:26393376 (GRCh38)
Gene constraint: LOEUF 0.646 · pLI 0.47 (gnomAD)
Structure: AlphaFold pLDDT 80.75 · 36 PDB
Residue 219: the protein kinase domain; an α-helix

Full CDK8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDK8 p.Ser62Leu Pathogenic ★★ same type
CDK8 p.Asn433Lys Uncertain significance ★★ ⚠ same type
CDK8 p.Met445Ile Uncertain significance ★★ ⚠ same type
CDK8 p.Pro388Gln Uncertain significance ★★ ⚠ same type
CDK8 c.934-28G>A Benign ★★ same type
CDK8 p.Ala188Gly Likely pathogenic ★ same type
CDK8 p.Arg178Gln Pathogenic ★ same type
CDK8 p.Asn156Ser Pathogenic ★ 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/cdk8-p-ala219val (accessed [today's date]).

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