Is CDK8 p.Pro388Gln (c.1163C>A) pathogenic?

CDK8 p.Pro388Gln (c.1163C>A) is classified Uncertain significance in CDK8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-21). AlphaMissense: likely benign (0.0848); Very rare (popmax 8.47e-05%, nfe); Associated with intellectual developmental disorder with hypotonia and behavioral abnormalities.

How common is CDK8 p.Pro388Gln (c.1163C>A) in the general population?

CDK8 p.Pro388Gln (c.1163C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CDK8 p.Pro388Gln (c.1163C>A)?

AlphaMissense predicts likely benign (score 0.0848) — an in-silico prediction, not a clinical call.

CDK8 p.Pro388Gln

Q: What condition is associated with CDK8 p.Pro388Gln (c.1163C>A)?

CDK8 p.Pro388Gln (c.1163C>A) is associated with intellectual developmental disorder with hypotonia and behavioral abnormalities, intellectual disability (ClinVar).

c.1163C>A · rs762174167 · VCV3068624

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0848 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with hypotonia and behavioral abnormalities

Computational evidence

Protein change
AlphaMissense	0.0848	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	LLR -6.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
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 0.76	unconstrained · MANE · 2,565 bp · p 0.018 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,018 alleles

Overall 6.84e-05% 1/1,461,864 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.Pro388Gln
Coding: c.1163C>A
MANE Select: NM_001260
dbSNP: rs762174167
Type: single nucleotide variant
Location: chr13:26401518 (GRCh38)
Gene constraint: LOEUF 0.646 · pLI 0.47 (gnomAD)
Structure: AlphaFold pLDDT 80.75 · 36 PDB
Residue 388: the 'disordered' region

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

Also linked: intellectual disability

Similar variants

CDK8 p.Ser62Leu Pathogenic ★★ same condition
CDK8 p.Asn433Lys Uncertain significance ★★ ⚠ same condition
CDK8 c.934-28G>A Benign ★★ same condition
CDK8 p.Ala188Gly Likely pathogenic ★ same condition
CDK8 p.Arg178Gln 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-pro388gln (accessed [today's date]).

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