Is CDK8 p.Ser62Ter (c.185C>A) pathogenic?

CDK8 p.Ser62Ter (c.185C>A) is classified Pathogenic in CDK8 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-16). Very rare (popmax 0.00174%, sas); Associated with Abnormal heart morphology.

What condition is associated with CDK8 p.Ser62Ter (c.185C>A)?

CDK8 p.Ser62Ter (c.185C>A) is associated with Abnormal heart morphology, congenital diaphragmatic hernia, Ebstein anomaly (ClinVar).

How common is CDK8 p.Ser62Ter (c.185C>A) in the general population?

CDK8 p.Ser62Ter (c.185C>A) is very rare (popmax 0.00174%, sas) (gnomAD).

CDK8 p.Ser62Ter

c.185C>A · rs1565977796 · VCV631491

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00174%, sas)

Conditions

Abnormal heart morphology

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 13
Splicing
SpliceAI	Δ0.38	donor loss · deltas
Pangolin	Δ0.38	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Overall
CADD	49.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00174% South Asian · 1/57,468 alleles

Overall 6.94e-05% 1/1,440,982 alleles · very rare exomes 1/1,288,946 · genomes 0/152,036 · joint denominator

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.Ser62Ter
Coding: c.185C>A
MANE Select: NM_001260
dbSNP: rs1565977796
Type: single nucleotide variant
Location: chr13:26337623 (GRCh38)
Gene constraint: LOEUF 0.646 · pLI 0.47 (gnomAD)
Structure: AlphaFold pLDDT 80.75 · 36 PDB
Residue 62: the protein kinase domain; a UniProt-annotated variant site (in iddhba; decreased protein kinase activity); an α-helix

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

Disease context

Abnormal heart morphology — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital diaphragmatic hernia Ebstein anomaly

Similar variants

CDK8 p.Ser62Leu Pathogenic ★★ same residue
CDK8 p.Ser62Trp Likely pathogenic ★ same residue
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

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-ser62ter (accessed [today's date]).

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