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…

MultiplemechanismLOEUF 1.50

Clinical Summary— HDDC3

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

17 VUS of 26 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?

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

This gene — mechanism propensity

0.76top 25%

GOF

0.6930th %ile

LOF

0.3066th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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

26 submitted variants in ClinVar

ClinVar

Classification Summary

VUS17

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	0	17	17
Likely Benign	1	0	1
Benign	0	0	0
Total	1	17	18

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

View in ClinVar →

43 pathogenic / likely-pathogenic (of 52) ClinVar copy-number / structural variants overlap HDDC3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →