HDDC3

Chr 15

HD domain containing 3

Also known as: (ppGpp)ase, MESH1, MYNRL15

NCBI Gene: 374659 ENSG00000184508 UniProt: Q8N4P3

The protein functions as a ppGpp hydrolyzing enzyme involved in cellular starvation response, with predicted guanosine-3',5'-bis(diphosphate) 3'-diphosphatase activity. Currently, no established human diseases have been associated with mutations in this gene. The gene shows low constraint to loss-of-function variation (pLI 0.02, LOEUF 1.5), suggesting it may be tolerant to heterozygous loss-of-function mutations.

ResearchSummary from RefSeq, UniProt

Predicted to enable guanosine-3',5'-bis(diphosphate) 3'-diphosphatase activity. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.50

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.50LOEUF

pLI 0.019

Z-score 0.82

OE 0.60 (0.27–1.50)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.39Z-score

OE missense 0.87 (0.70–1.08)

58 obs / 66.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.60 (0.27–1.50)

0≤0.351.4

Missense OE?0.87 (0.70–1.08)

0≤0.61.4

Synonymous OE?0.78

0≤1.21.6

LoF obs/exp: 3 / 5.0Missense obs/exp: 58 / 66.9Syn Z: 0.95

Background carrier burden — how many people carry a rare variant somewhere in HDDC3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 240

312 rare PASS variants

Rare truncating (LoF)

1 in 750

74 rare PASS variants

Rare synonymous (reference)

1 in 380

120 rare PASS variants

Rare missense and truncating variants are carried at similar rates in HDDC3; this gene does not show strong loss-of-function constraint by this measure. 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)	~556k	1 in 310	1 in 1,400
South Asian	~43k	1 in 170	1 in 600
Remaining (unassigned)	~30k	1 in 210	1 in 640
European (Finnish)	~27k	1 in 1,600	1 in 1,900
Admixed American	~22k	1 in 200	1 in 850
African / African American	~21k	1 in 250	1 in 560
East Asian	~20k	1 in 210	1 in 1,300
Ashkenazi Jewish	~13k	≈ 1 in 2,900	1 in 1,100
Middle Eastern	~2,884	1 in 570	1 in 490

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): 3 of 4 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 4.? see exons ↓