HECTD4

Chr 12AR

HECT domain E3 ubiquitin protein ligase 4

Also known as: C12ord51, C12orf51, HEEL, NEDSSCC, POTAGE

NCBI Gene: 283450 ENSG00000173064 UniProt: Q9Y4D8 OMIM: 620209

The protein functions as an E3 ubiquitin-protein ligase that transfers ubiquitin to targeted substrates and is involved in glucose homeostasis. Biallelic mutations cause autosomal recessive neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum. The gene is highly constrained against loss-of-function variants, indicating it is essential for normal cellular function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Predicted to enable ubiquitin-protein transferase activity. Involved in glucose homeostasis and glucose metabolic process. Predicted to be located in membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.131 OMIM phenotype

Clinical Summary— HECTD4

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 451 VUS of 582 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.13LOEUF

pLI 1.000

Z-score 12.02

OE 0.08 (0.06–0.13)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

6.94Z-score

OE missense 0.60 (0.57–0.63)

1429 obs / 2382.6 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.08 (0.06–0.13)

0≤0.351.4

Missense OE?0.60 (0.57–0.63)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 17 / 200.7Missense obs/exp: 1429 / 2382.6Syn Z: 1.43

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateHECTD4-related neurodevelopmental disorder with seizures, hypotonia, spasticity, and agenesis of the corpus callosumOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.3196th %ile

GOF

0.3094th %ile

LOF

0.74top 10%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

582 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic4

VUS451

Likely Benign40

Benign6

Pathogenic

Likely Pathogenic

451

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	2	0	0	5
Likely Pathogenic	4	0	0	0	4
VUS	1	446	3	1	451
Likely Benign	1	13	2	24	40
Benign	0	0	0	6	6
Total	9	461	5	31	506

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 9) ClinVar copy-number / structural variants overlap HECTD4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →