KDM8

Chr 16

lysine demethylase 8

Also known as: JMJD5

NCBI Gene: 79831 ENSG00000155666 UniProt: Q8N371 OMIM: 611917

KDM8 encodes a bifunctional enzyme that acts as both an endopeptidase cleaving histone N-terminal tails and a 2-oxoglutarate-dependent monooxygenase, playing critical roles in transcriptional regulation, mitosis, cell cycle progression, and circadian gene expression. The gene shows very low constraint to loss-of-function variants (pLI = 0.00003, LOEUF = 0.836), suggesting tolerance to haploinsufficiency. No established Mendelian diseases have been associated with KDM8 mutations in pediatric populations.

OMIM ResearchSummary from RefSeq, UniProt

This gene likely encodes a histone lysine demethylase. Studies of a similar protein in mouse indicate a potential role for this protein as a tumor suppressor. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2009]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.84

Clinical Summary— KDM8

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

68 VUS of 100 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.84LOEUF

pLI 0.000

Z-score 2.14

OE 0.50 (0.32–0.84)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.61Z-score

OE missense 0.90 (0.81–0.99)

247 obs / 275.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.32–0.84)

0≤0.351.4

Missense OE?0.90 (0.81–0.99)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 11 / 21.8Missense obs/exp: 247 / 275.7Syn Z: -0.04

This gene — mechanism propensity

0.6551th %ile

GOF

0.5465th %ile

LOF

0.2678th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

100 submitted variants in ClinVar

ClinVar

Classification Summary

VUS68

Likely Benign12

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	67	1	0	68
Likely Benign	11	0	1	12
Benign	0	0	0	0
Total	78	1	1	80

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

31 pathogenic / likely-pathogenic (of 44) ClinVar copy-number / structural variants overlap KDM8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →