Is CDK8 p.Asp421His (c.1261G>C) pathogenic?

CDK8 p.Asp421His (c.1261G>C) is classified Uncertain significance in CDK8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-29). AlphaMissense: likely pathogenic (0.8224); Absent from gnomAD v4.1; Associated with intellectual developmental disorder with hypotonia and behavioral abnormalities.

How common is CDK8 p.Asp421His (c.1261G>C) in the general population?

CDK8 p.Asp421His (c.1261G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDK8 p.Asp421His (c.1261G>C)?

AlphaMissense predicts likely pathogenic (score 0.8224) — an in-silico prediction, not a clinical call.

CDK8 p.Asp421His

Q: What condition is associated with CDK8 p.Asp421His (c.1261G>C)?

CDK8 p.Asp421His (c.1261G>C) is associated with intellectual developmental disorder with hypotonia and behavioral abnormalities (ClinVar).

c.1261G>C · rs2138075822 · VCV2431811

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8224 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual developmental disorder with hypotonia and behavioral abnormalities

Computational evidence

Protein change
AlphaMissense	0.8224	likely pathogenic
REVEL	0.35	indeterminate
SaProt	LLR -5.66	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 2,565 bp · p 0.018 · regional, not allelic
Overall
CADD	29.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDK8
Protein: p.Asp421His
Coding: c.1261G>C
MANE Select: NM_001260
dbSNP: rs2138075822
Type: single nucleotide variant
Location: chr13:26401616 (GRCh38)
Gene constraint: LOEUF 0.646 · pLI 0.47 (gnomAD)
Structure: AlphaFold pLDDT 80.75 · 36 PDB
Residue 421: 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

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.Arg178Gln Pathogenic ★ same condition
CDK8 p.Asp173His Likely pathogenic ★ same condition
CDK8 p.Gly30Val 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-asp421his (accessed [today's date]).

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