HACE1

Chr 6AR

HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1

Also known as: SPPRS

NCBI Gene: 57531 ENSG00000085382 UniProt: Q8IYU2 OMIM: 610876

The protein is an E3 ubiquitin ligase that regulates Golgi membrane dynamics during cell division and mediates degradation of active RAC1, playing roles in cellular trafficking and host defense. Mutations cause autosomal recessive spastic paraplegia and psychomotor retardation with or without seizures. The gene is highly constrained against loss-of-function variants (LOEUF 0.524), suggesting complete loss of function is not well tolerated.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a HECT domain and ankyrin repeat-containing ubiquitin ligase. The encoded protein is involved in specific tagging of target proteins, leading to their subcellular localization or proteasomal degradation. The protein is a potential tumor suppressor and is involved in the pathophysiology of several tumors, including Wilm's tumor. [provided by RefSeq, Mar 2016]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.521 OMIM phenotype

Clinical Summary— HACE1

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Population Constraint (gnomAD)

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

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ClinVar Variants

40 unique Pathogenic / Likely Pathogenic· 120 VUS of 352 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.52LOEUF

pLI 0.000

Z-score 4.35

OE 0.36 (0.25–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.59Z-score

OE missense 0.54 (0.49–0.60)

259 obs / 480.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.36 (0.25–0.52)

0≤0.351.4

Missense OE?0.54 (0.49–0.60)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 19 / 53.2Missense obs/exp: 259 / 480.7Syn Z: -0.47

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveHACE1-related disorderLOFAR

This gene — mechanism propensity

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

0.6745th %ile

GOF

0.7029th %ile

LOF

0.2971th %ile

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.

ClinVar Variant Classifications

352 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23

Likely Pathogenic17

VUS120

Likely Benign146

Benign19

Conflicting4

Pathogenic

Likely Pathogenic

120

VUS

146

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	17	1	5	0	23
Likely Pathogenic	14	3	0	0	17
VUS	1	106	10	3	120
Likely Benign	0	5	63	78	146
Benign	0	1	12	6	19
Conflicting	—				4
Total	32	116	90	87	329

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap HACE1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →