KDM5D

Chr Y

lysine demethylase 5D

Also known as: HY, HYA, JARID1D, SMCY

NCBI Gene: 8284 ENSG00000012817 UniProt: Q9BY66 OMIM: 426000

The encoded protein is a histone demethylase that specifically removes methyl groups from lysine-4 of histone H3, playing a central role in gene expression regulation and transcriptional repression. KDM5D is located on the Y chromosome and follows Y-linked inheritance, meaning mutations are passed from fathers to sons only. The gene is highly constrained against loss-of-function variants, but specific disease associations have not been established in the provided data.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein containing zinc finger domains. A short peptide derived from this protein is a minor histocompatibility antigen which can lead to graft rejection of male donor cells in a female recipient. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.36

LOEUF

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.36LOEUF

pLI 0.928

Z-score 3.71

OE 0.14 (0.06–0.36)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.37Z-score

OE missense 1.07 (0.96–1.18)

259 obs / 242.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.14 (0.06–0.36)

0≤0.351.4

Missense OE?1.07 (0.96–1.18)

0≤0.61.4

Synonymous OE?1.39

0≤1.21.6

LoF obs/exp: 3 / 21.6Missense obs/exp: 259 / 242.7Syn Z: -2.81

Background carrier burden — how many people carry a rare variant somewhere in KDM5D?

gnomAD v4 · ~363k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

461 rare PASS variants

Rare truncating (LoF)

1 in 3,300

36 rare PASS variants

Rare synonymous (reference)

1 in 150

198 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KDM5D. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~270k	1 in 180	1 in 2,900
South Asian	~32k	1 in 180	none seen
Remaining (unassigned)	~14k	1 in 250	≈ 1 in 14,000
European (Finnish)	~13k	1 in 900	none seen
Admixed American	~9,515	1 in 140	1 in 1,900
East Asian	~9,494	1 in 150	1 in 620
African / African American	~9,007	1 in 120	≈ 1 in 6,900
Ashkenazi Jewish	~6,747	≈ 1 in 1,700	none seen
Middle Eastern	~1,631	1 in 320	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 0 of 26 coding exons well covered in gnomAD exomes; exons 2, 3, 4, 5, 6 and 21 more poorly covered. Genomes: 0 of 26 (exons 2, 3, 4, 5, 6 and 21 more below).? see exons ↓