Is CDK8 p.Arg178Gln (c.533G>A) pathogenic?

CDK8 p.Arg178Gln (c.533G>A) is classified Pathogenic in CDK8 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-02-05). AlphaMissense: likely pathogenic (0.9989); Very rare (popmax 0.000255%, nfe); Associated with intellectual developmental disorder with hypotonia and behavioral abnormalities.

How common is CDK8 p.Arg178Gln (c.533G>A) in the general population?

CDK8 p.Arg178Gln (c.533G>A) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about CDK8 p.Arg178Gln (c.533G>A)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

CDK8 p.Arg178Gln

Q: What condition is associated with CDK8 p.Arg178Gln (c.533G>A)?

CDK8 p.Arg178Gln (c.533G>A) is associated with intellectual developmental disorder with hypotonia and behavioral abnormalities (ClinVar).

c.533G>A · VCV3358926

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with hypotonia and behavioral abnormalities

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic ✓ concordant with ClinVar
REVEL	0.726	pathogenic-leaning
SaProt	LLR -13.50	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 130 kb · p 6.4e-10 · regional, not allelic
Overall
CADD	34.0	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 0.000255% European (non-Finnish) · 3/1,178,148 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000206% 3/1,457,098 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.Arg178Gln
Coding: c.533G>A
MANE Select: NM_001260
Type: single nucleotide variant
Location: chr13:26385229 (GRCh38)
Gene constraint: LOEUF 0.646 · pLI 0.47 (gnomAD)
Structure: AlphaFold pLDDT 80.75 · 36 PDB
Residue 178: the protein kinase domain; a UniProt-annotated variant site (in iddhba; decreased protein kinase activity); a turn

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

Disease context

intellectual developmental disorder with hypotonia and behavioral abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDK8 p.Ser62Leu Pathogenic ★★ same condition
CDK8 p.Asn433Lys Uncertain significance ★★ ⚠ same condition
CDK8 p.Pro388Gln Uncertain significance ★★ ⚠ same condition
CDK8 c.934-28G>A Benign ★★ same condition
CDK8 p.Ala188Gly Likely pathogenic ★ same condition
CDK8 p.Asp173His Likely pathogenic ★ same condition
CDK8 p.Gly30Val Likely pathogenic ★ same condition
CDK8 p.His34Pro Likely pathogenic ★ 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-arg178gln (accessed [today's date]).

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