Is CDK8 p.Asp42His (c.124G>C) pathogenic?

CDK8 p.Asp42His (c.124G>C) is classified Uncertain significance in CDK8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-02). AlphaMissense: likely pathogenic (0.7087); Very rare (popmax 0.000678%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CDK8 p.Asp42His (c.124G>C)?

CDK8 p.Asp42His (c.124G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CDK8 p.Asp42His (c.124G>C) in the general population?

CDK8 p.Asp42His (c.124G>C) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about CDK8 p.Asp42His (c.124G>C)?

AlphaMissense predicts likely pathogenic (score 0.7087) — an in-silico prediction, not a clinical call.

CDK8 p.Asp42His

c.124G>C · VCV4224661

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7087 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7087	likely pathogenic
REVEL	0.206	benign-leaning
SaProt	LLR -12.69	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 130 kb · p 6.4e-10 · regional, not allelic
Overall
CADD	28.3	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 0.000678% European (non-Finnish) · 8/1,179,108 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,611,988 alleles · very rare

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.Asp42His
Coding: c.124G>C
MANE Select: NM_001260
Type: single nucleotide variant
Location: chr13:26254765 (GRCh38)
Gene constraint: LOEUF 0.646 · pLI 0.47 (gnomAD)
Structure: AlphaFold pLDDT 80.75 · 36 PDB
Residue 42: the protein kinase domain; a β-strand

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.Asp42Asn Likely benign ★ 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.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-asp42his (accessed [today's date]).

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