HECTD4

protein-coding

HECT domain E3 ubiquitin protein ligase 4, the group of MicroRNA protein coding host genes|HECT domain containing

Gene summary

Predicted to enable ubiquitin protein ligase activity. Involved in glucose homeostasis and glucose metabolic process. Predicted to be located in membrane. [provided by Alliance of Genome Resources, Jun 2026]

Previous symbols:

C12orf51

MANE transcript

NM_001388303.1

Inheritance

ClinVar variants

P:12U:515B:67

Top phenotype

Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr12:112,160,188-112,382,439

External References & Databases

Ensembl (ENSG00000173064)

Transcript & Mutation Effects

hg38 • Region Span ~222.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosumMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859516

Submitter: G2P

neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosumLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859516

Submitter: Ambry Genetics

neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosumSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859516

Submitter: PanelApp Australia

neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosumMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859516

Submitter: Broad Center for Mendelian Genomics

neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosumMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859516

Submitter: Baylor College of Medicine Research Center

neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosumSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859516

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosumAR

Manifestation: Craniofacial; Dental; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 36401616

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HECTD4 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 470

not providedTotal: 69

HECTD4-related disorderTotal: 28

Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosumTotal: 24

Autism spectrum disorderTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001388303.1. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			13 clinvar	48 clinvar	5 clinvar	66
missense	2 clinvar		465 clinvar	14 clinvar		481
nonsense	3 clinvar	1 clinvar	10 clinvar			14
start loss						0
frameshift	2 clinvar	2 clinvar	2 clinvar			6
splice donor/acceptor (+/-2bp)		2 clinvar	25 clinvar			27
Total	7	5	515	62	5	594

Highest pathogenic variant AF is 0.00017912927

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001388303.1	RefSeq	NP_001375232.1	76	MANE Select
ENST00000682272.1	Ensembl	ENSP00000507687.1	76	MANE Select
NM_001109662.4	RefSeq	NP_001103132.4	76	Standard
ENST00000377560.10	Ensembl	ENSP00000366783.7	76	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

glucose metabolic process
protein ubiquitination
glucose homeostasis

Molecular Function

ubiquitin-protein transferase activity

Cellular Component

integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000550722
Coding exons: 75
Length: 221905
Individuals with no LoFs: 125530
Homozygous LoFs: 0
Heterozygous LoFs: 63
Defined: 125593
p: 0.000251

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	6.94	1429	2.38e+3	0.600	0.000144	27641
Missense (PolyPhen)		414	847.44	0.48853		9521
Synonymous	1.43	933	990	0.942	0.0000657	8703
Loss of Function	12.0	17	201	0.0847	0.0000114	2327

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00026	0.00025	rare
Latino/Admixed American	0.00024	0.00017	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00012	0.00011	rare
Finnish	0.00033	0.00032	rare
European (Non-Finnish)	0.00040	0.00034	rare
South Asian	0.000067	0.000065	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. {ECO:0000250}.;

Recessive Scores

pRec: 0.110

Essentials

Essential (CRISPR2): N

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium