HECTD1

Summary

HECTD1 (HECT domain E3 ubiquitin protein ligase 1, HGNC:20157) is a protein-coding gene on chromosome 14q12, encoding E3 ubiquitin-protein ligase HECTD1 (Q9ULT8). 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. It is a selective cancer dependency (DepMap: 34.5% of cell lines).

Enables ubiquitin protein ligase activity. Predicted to be involved in positive regulation of proteasomal ubiquitin-dependent protein catabolic process. Predicted to act upstream of or within several processes, including chordate embryonic development; circulatory system development; and protein ubiquitination.

Source: NCBI Gene 25831 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Moderate, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 312 total — 2 pathogenic, 1 likely-pathogenic
• Cancer dependency (DepMap): dependent in 34.5% of screened cell lines
• MANE Select transcript: NM_015382

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20157
Approved symbol	HECTD1
Name	HECT domain E3 ubiquitin protein ligase 1
Location	14q12
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1131
Ensembl gene	ENSG00000092148
Ensembl biotype	protein_coding
OMIM	618649
Entrez	25831

Gene structure

Transcript identifiers

Ensembl transcripts: 52 — 30 protein_coding, 18 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000399332, ENST00000553616, ENST00000553700, ENST00000553957, ENST00000554027, ENST00000554471, ENST00000554850, ENST00000554882, ENST00000555311, ENST00000555843, ENST00000555915, ENST00000556004, ENST00000556224, ENST00000556281, ENST00000556474, ENST00000557321, ENST00000557695, ENST00000611816, ENST00000686883, ENST00000687002, ENST00000688459, ENST00000688933, ENST00000689382, ENST00000691123, ENST00000691390, ENST00000692014, ENST00000692132, ENST00000692835, ENST00000693537, ENST00000693685, ENST00000860796, ENST00000860797, ENST00000860798, ENST00000860799, ENST00000931520, ENST00000931521, ENST00000931522, ENST00000931523, ENST00000931524, ENST00000931525, ENST00000972012, ENST00000972013, ENST00000972014, ENST00000972015, ENST00000972016, ENST00000972017, ENST00000972018, ENST00000972019, ENST00000972020, ENST00000972021, ENST00000972022, ENST00000972023

RefSeq mRNA: 2 — MANE Select: NM_015382 NM_001411010, NM_015382

CCDS: CCDS41939, CCDS91860

Canonical transcript exons

ENST00000399332 — 43 exons

Exon	Start	End
ENSE00003523810	31119710	31119866
ENSE00003573589	31113877	31114059
ENSE00003582028	31105383	31105476
ENSE00003597438	31106646	31107253
ENSE00003606468	31116236	31116458
ENSE00003614913	31113104	31113189
ENSE00003622690	31101180	31101324
ENSE00003624135	31107567	31107704
ENSE00003629539	31114286	31114340
ENSE00003637840	31205797	31205957
ENSE00003640078	31109397	31109598
ENSE00003647394	31113277	31113484
ENSE00003659261	31102916	31103066
ENSE00003667862	31105590	31105668
ENSE00003675749	31121383	31121505
ENSE00003685204	31112416	31112543
ENSE00003690986	31122914	31123047
ENSE00003847849	31100117	31101067
ENSE00003850410	31207016	31207793
ENSE00003889369	31133509	31133675
ENSE00003889407	31135476	31135615
ENSE00003889556	31173525	31173806
ENSE00003890222	31134872	31135195
ENSE00003890447	31171861	31171959
ENSE00003890699	31136531	31136665
ENSE00003891210	31144111	31144257
ENSE00003891318	31133238	31133414
ENSE00003891552	31157165	31157303
ENSE00003891929	31148721	31148797
ENSE00003892031	31141858	31141952
ENSE00003893134	31127785	31128006
ENSE00003893271	31172046	31172122
ENSE00003894251	31144807	31144941
ENSE00003894303	31169354	31169468
ENSE00003894334	31156840	31157010
ENSE00003894537	31139892	31139997
ENSE00003894549	31173156	31173426
ENSE00003895064	31149999	31150221
ENSE00003895122	31148897	31149160
ENSE00003895546	31178020	31178254
ENSE00003895658	31128612	31129448
ENSE00003895701	31168298	31168472
ENSE00003895873	31174911	31175138

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 99.54.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.9980 / max 682.9443, expressed in 1817 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142732	13.9395	1788
142733	7.4471	1735
142731	4.8455	1659
142730	1.9545	1148
142735	0.5991	338
142736	0.5244	274
142734	0.3505	129
142727	0.3375	124

Top tissues by expression

256 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tibialis anterior	UBERON:0001385	99.54	gold quality
deltoid	UBERON:0001476	99.16	gold quality
ileal mucosa	UBERON:0000331	98.77	gold quality
calcaneal tendon	UBERON:0003701	98.72	gold quality
gastrocnemius	UBERON:0001388	98.69	gold quality
lower esophagus mucosa	UBERON:0035834	98.65	gold quality
muscle of leg	UBERON:0001383	98.59	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.56	gold quality
upper arm skin	UBERON:0004263	98.48	gold quality
tendon	UBERON:0000043	98.44	gold quality
biceps brachii	UBERON:0001507	98.44	gold quality
skeletal muscle tissue	UBERON:0001134	98.43	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.40	gold quality
vastus lateralis	UBERON:0001379	98.35	gold quality
quadriceps femoris	UBERON:0001377	98.32	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.31	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.26	gold quality
upper leg skin	UBERON:0004262	98.22	gold quality
left ventricle myocardium	UBERON:0006566	98.20	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	98.04	gold quality
kidney epithelium	UBERON:0004819	97.99	gold quality
adrenal tissue	UBERON:0018303	97.89	gold quality
muscle tissue	UBERON:0002385	97.87	gold quality
nasal cavity epithelium	UBERON:0005384	97.85	gold quality
esophagus squamous epithelium	UBERON:0006920	97.80	gold quality
esophagus mucosa	UBERON:0002469	97.79	gold quality
bronchial epithelial cell	CL:0002328	97.71	gold quality
tendon of biceps brachii	UBERON:0008188	97.52	gold quality
bronchus	UBERON:0002185	97.49	gold quality
skin of abdomen	UBERON:0001416	97.48	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 34.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 13)

• HectD1 promotes the APC-Axin interaction to negatively regulate Wnt signaling. (PMID:23277359)
• our high-resolution structures show a new fold composed of five small helices where H3 and H4 are tilted in a novel arrangement; we call this fold the Basic Tilted Helix Bundle (BTHB) domain. (PMID:24667607)
• Hectd1 regulates the protein level of IQGAP1 through ubiquitination. (PMID:28073378)
• HECTD1 may be involved in the regulation of ABCA1-mediated cholesterol export from unloaded macrophages to apoA-I. (PMID:29306077)
• SiO2 concomitantly increased circHECTD1 expression, which, in turn, inhibited HECTD1 protein expression. (PMID:29540674)
• we have now identified HECTD1 as an important factor in promoting Base excision repair (BER) in chromatin. (PMID:31799632)
• HECTD1 regulates the expression of SNAIL: Implications for epithelialmesenchymal transition. (PMID:32319576)
• CircHECTD1 up-regulates mucin 1 expression to accelerate hepatocellular carcinoma development by targeting microRNA-485-5p via a competing endogenous RNA mechanism. (PMID:32675746)
• Circular RNA circHECTD1 facilitates glioma progression by regulating the miR-296-3p/SLC10A7 axis. (PMID:33561315)
• The deubiquitinase TRABID stabilizes the K29/K48-specific E3 ubiquitin ligase HECTD1. (PMID:33853758)
• The E3 ubiquitin ligase HECTD1 contributes to cell proliferation through an effect on mitosis. (PMID:35915203)
• Nucleoporin 93, a new substrate of the E3 ubiquitin protein ligase HECTD1, promotes esophageal squamous cell carcinoma progression. (PMID:37993750)
• Identification and functional analysis of rare HECTD1 missense variants in human neural tube defects. (PMID:38451291)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hectd1	ENSDARG00000054213
mus_musculus	Hectd1	ENSMUSG00000035247
rattus_norvegicus	Hectd1	ENSRNOG00000006905
drosophila_melanogaster	Ufd4	FBGN0032208
caenorhabditis_elegans		WBGENE00016405

Paralogs (24): HECW1 (ENSG00000002746), UBE3C (ENSG00000009335), NEDD4L (ENSG00000049759), NEDD4 (ENSG00000069869), ITCH (ENSG00000078747), HACE1 (ENSG00000085382), HUWE1 (ENSG00000086758), UBR5 (ENSG00000104517), SMURF2 (ENSG00000108854), UBE3A (ENSG00000114062), AREL1 (ENSG00000119682), WWP1 (ENSG00000123124), HERC2 (ENSG00000128731), HECW2 (ENSG00000138411), HERC3 (ENSG00000138641), HERC6 (ENSG00000138642), HERC5 (ENSG00000138646), HERC4 (ENSG00000148634), UBE3B (ENSG00000151148), TRIP12 (ENSG00000153827), HECTD2 (ENSG00000165338), HECTD4 (ENSG00000173064), WWP2 (ENSG00000198373), SMURF1 (ENSG00000198742)

Protein

Protein identifiers

E3 ubiquitin-protein ligase HECTD1 — Q9ULT8 (reviewed: Q9ULT8)

Alternative names: E3 ligase for inhibin receptor, HECT domain-containing protein 1

All UniProt accessions (10): Q9ULT8, A0A087X2H1, A0A8I5KU01, A0A8I5KUD6, A0A8I5QJE9, A0A8I5QJU2, G3V4V5, H0YJ72, H0YJD4, H0YJP0

UniProt curated annotations — full annotation on UniProt →

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. Mediates ‘Lys-63’-linked polyubiquitination of HSP90AA1 which leads to its intracellular localization and reduced secretion. Negatively regulating HSP90AA1 secretion in cranial mesenchyme cells may impair their emigration and may be essential for the correct development of the cranial neural folds and neural tube closure. Catalyzes ubiquitination and degradation of ZNF622, an assembly factor for the ribosomal 60S subunit, in hematopoietic cells, thereby promoting hematopoietic stem cell renewal.

Subunit / interactions. Interacts with IGSF1.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the UPL family. K-HECT subfamily.

RefSeq proteins (2): NP_001397939, NP_056197* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000569	HECT_dom	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR010606	Mib_Herc2	Domain
IPR011989	ARM-like	Homologous_superfamily
IPR012919	SUN_dom	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR035983	Hect_E3_ubiquitin_ligase	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR037252	Mib_Herc2_sf	Homologous_superfamily
IPR041200	FKBP3_BTHB	Domain
IPR045322	HECTD1/TRIP12-like	Family

Pfam: PF00632, PF06701, PF07738, PF12796, PF18410

UniProt features (67 total): region of interest 12, compositionally biased region 11, modified residue 8, sequence conflict 8, helix 8, strand 6, repeat 4, turn 3, sequence variant 2, domain 2, chain 1, active site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3DKM	X-RAY DIFFRACTION	1.6
2DK3	SOLUTION NMR
2LC3	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9ULT8-F1	69.07	0.16

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 2579 (glycyl thioester intermediate)

Post-translational modifications (8): 631, 640, 1384, 1488, 1567, 1760, 1772, 2318

Mutagenesis-validated functional residues (1):

Position	Phenotype
2579	abolished e3 ubiquitin-protein ligase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 237 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, AHRARNT_01, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GCM_GSPT1, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_MATURE_CELL, TATTATA_MIR374, GOBP_ARTERY_DEVELOPMENT

GO Biological Process (6): heart valve development (GO:0003170), ventricular septum development (GO:0003281), ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), aorta development (GO:0035904)

GO Molecular Function (5): metal ion binding (GO:0046872), ubiquitin protein ligase activity (GO:0061630), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (0):

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
heart development	1
anatomical structure development	1
cardiac ventricle development	1
cardiac septum development	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
protein modification by small protein conjugation	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
artery development	1
cation binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein transferase activity	1
binding	1
catalytic activity	1

Protein interactions and networks

STRING

1268 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HECTD1	APC2	O95996	345
HECTD1	DYM	Q7RTS9	322
HECTD1	RNF146	Q9NTX7	320
HECTD1	UBR4	Q5T4S7	315
HECTD1	HID1	Q8IV36	314
HECTD1	ZCCHC17	Q9NP64	308
HECTD1	SACS	Q9NZJ4	306
HECTD1	AMOTL1	Q8IY63	306
HECTD1	C1QTNF5	Q9BXJ0	292
HECTD1	LTN1	O94822	286
HECTD1	APC	P25054	282
HECTD1	PHACTR1	Q9C0D0	278
HECTD1	PNN	Q9H307	276
HECTD1	TIPARP	Q7Z3E1	268
HECTD1	PPP1R26	Q5T8A7	264

IntAct

122 interactions, top by confidence:

A	B	Type	Score
BMI1	CBX4	psi-mi:“MI:0914”(association)	0.900
HIF1AN	APBA3	psi-mi:“MI:0914”(association)	0.850
GMNN	MCIDAS	psi-mi:“MI:0914”(association)	0.770
rep	MPHOSPH10	psi-mi:“MI:0914”(association)	0.660
HIF1AN	GMDS	psi-mi:“MI:0914”(association)	0.640
TTLL1	CDC27	psi-mi:“MI:0914”(association)	0.640
CINP	KIF7	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
CAPN6	UBA6	psi-mi:“MI:0914”(association)	0.530
ZNF223	PPM1G	psi-mi:“MI:0914”(association)	0.530
CAMKMT	COL1A1	psi-mi:“MI:0914”(association)	0.530
BMP15	AMD1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
EPB41L5	SETD1A	psi-mi:“MI:0914”(association)	0.530
CINP	CHMP2A	psi-mi:“MI:0914”(association)	0.530
ZNF223	CENPB	psi-mi:“MI:0914”(association)	0.530
ZNF738	TRIM28	psi-mi:“MI:0914”(association)	0.530
B9D2	ANKRD40	psi-mi:“MI:0914”(association)	0.530
DIRAS3	DCAF10	psi-mi:“MI:0914”(association)	0.530
SSH2	HECTD1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (1142): ZRANB1 (Affinity Capture-Western), HECTD1 (Affinity Capture-MS), HECTD1 (Affinity Capture-MS), HECTD1 (Affinity Capture-MS), HECTD1 (Affinity Capture-MS), HECTD1 (Affinity Capture-MS), HECTD1 (Affinity Capture-MS), HECTD1 (Affinity Capture-MS), HECTD1 (Affinity Capture-MS), HECTD1 (Affinity Capture-MS), HECTD1 (Affinity Capture-MS), HECTD1 (Affinity Capture-MS), HECTD1 (Affinity Capture-MS), HECTD1 (Two-hybrid), HECTD1 (Affinity Capture-MS)

ESM2 similar proteins: A0A072VIM5, A0A0K0PU92, A2CIR7, F4IG73, F4JD14, G3LSH3, G8GTN7, O23052, O42132, O80560, P03372, P0CI65, P19785, P48423, P50242, P57717, P57753, Q0JJ01, Q29040, Q2HW56, Q2QXZ2, Q2RAQ5, Q337A0, Q53AD2, Q5D0W8, Q5YLM1, Q5ZLG9, Q69ZR2, Q6KAE5, Q6NLQ8, Q6PJI9, Q6WQJ1, Q7EZ44, Q7Z494, Q8C0M0, Q8CFE5, Q8IPH9, Q8IZ41, Q9CAJ9, Q9FDY4

Diamond homologs: A0A1D8PNZ7, A2X8A7, A2XNL6, A2Y8U6, P43585, P77736, Q02979, Q10003, Q10B79, Q21407, Q2V4F9, Q658H5, Q680A6, Q6EPQ3, Q74ZH9, Q80VJ4, Q8C0L9, Q8RB32, Q94A21, Q9NPB8, Q9SGA2, Q9ULT8, A1CQG2, A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B4F6W9, B8N7E5, D3ZBM7, E1B7Q7, E1C656, F1LP64, F1N6G5, F1RCR6, F8W2M1, G0S9J5, G5E870, O00308

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
HECTD1	“down-regulates quantity”	HSP90AA1	ubiquitination
Ub:E2	“up-regulates activity”	HECTD1	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 142 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	7	55.5×	5e-09
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	49.0×	8e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	49.0×	8e-09
Activation of BH3-only proteins	7	36.2×	6e-08
Intrinsic Pathway for Apoptosis	8	24.4×	8e-08
RHO GTPases activate PKNs	7	23.1×	1e-06
Apoptosis	10	17.5×	3e-08
FOXO-mediated transcription	5	17.5×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	10	8.4×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

312 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	254
Likely benign	9
Benign	12

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
3897585	NM_015382.4(HECTD1):c.3670G>T (p.Gly1224Ter)	Pathogenic
4056324	NM_015382.4(HECTD1):c.3109A>T (p.Lys1037Ter)	Pathogenic
4686815	NM_015382.4(HECTD1):c.3635_3636del (p.His1212fs)	Likely pathogenic

SpliceAI

6788 predictions. Top by Δscore:

Variant	Effect	Δscore
14:31101063:TCAAC:T	acceptor_gain	1.0000
14:31101064:CAAC:C	acceptor_gain	1.0000
14:31101064:CAACC:C	acceptor_gain	1.0000
14:31101066:ACCT:A	acceptor_loss	1.0000
14:31101067:CCT:C	acceptor_loss	1.0000
14:31101069:T:C	acceptor_loss	1.0000
14:31102911:CATA:C	donor_loss	1.0000
14:31102912:ATAC:A	donor_loss	1.0000
14:31102913:TA:T	donor_loss	1.0000
14:31102914:ACCT:A	donor_loss	1.0000
14:31102915:C:CA	donor_loss	1.0000
14:31102915:CCTG:C	donor_gain	1.0000
14:31103062:CCCAT:C	acceptor_gain	1.0000
14:31103063:CCATC:C	acceptor_gain	1.0000
14:31103070:CATCG:C	acceptor_gain	1.0000
14:31103073:CG:C	acceptor_gain	1.0000
14:31103074:G:C	acceptor_gain	1.0000
14:31103074:G:GC	acceptor_gain	1.0000
14:31103077:CATG:C	acceptor_gain	1.0000
14:31103078:A:AC	acceptor_gain	1.0000
14:31103078:A:C	acceptor_gain	1.0000
14:31103080:G:GC	acceptor_gain	1.0000
14:31103084:C:CT	acceptor_gain	1.0000
14:31103085:G:T	acceptor_gain	1.0000
14:31103090:C:CT	acceptor_gain	1.0000
14:31103092:C:CT	acceptor_gain	1.0000
14:31103093:A:T	acceptor_gain	1.0000
14:31105378:ATTAC:A	donor_loss	1.0000
14:31105379:TTACC:T	donor_loss	1.0000
14:31105380:TA:T	donor_loss	1.0000

AlphaMissense

17054 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:31100942:A:C	F2607L	1.000
14:31100942:A:T	F2607L	1.000
14:31100943:A:G	F2607S	1.000
14:31100944:A:G	F2607L	1.000
14:31100970:A:G	L2598P	1.000
14:31101009:A:G	L2585S	1.000
14:31101015:A:G	L2583P	1.000
14:31101015:A:T	L2583H	1.000
14:31101019:A:C	Y2582D	1.000
14:31101032:A:C	N2577K	1.000
14:31101032:A:T	N2577K	1.000
14:31101190:A:T	V2562D	1.000
14:31101196:A:G	L2560P	1.000
14:31101196:A:T	L2560H	1.000
14:31101252:A:C	F2541L	1.000
14:31101252:A:T	F2541L	1.000
14:31101253:A:G	F2541S	1.000
14:31101254:A:G	F2541L	1.000
14:31101262:A:G	F2538S	1.000
14:31101307:A:G	F2523S	1.000
14:31101315:G:C	F2520L	1.000
14:31101315:G:T	F2520L	1.000
14:31101316:A:G	F2520S	1.000
14:31101317:A:G	F2520L	1.000
14:31102929:A:C	Y2513D	1.000
14:31102932:C:G	G2512R	1.000
14:31102974:A:G	W2498R	1.000
14:31102974:A:T	W2498R	1.000
14:31107099:T:A	D2258V	1.000
14:31107100:C:G	D2258H	1.000

dbSNP variants (sampled 300 via entrez): RS1000008287 (14:31118999 C>T), RS1000010869 (14:31160918 C>T), RS1000058581 (14:31202025 G>A), RS1000095089 (14:31133669 A>T), RS1000110630 (14:31126395 T>C), RS1000159287 (14:31184794 A>G), RS1000161504 (14:31202701 G>C,T), RS1000166854 (14:31169039 A>C), RS1000193098 (14:31146323 C>A), RS1000213248 (14:31110357 T>C), RS1000281156 (14:31166024 T>G), RS1000330410 (14:31182472 C>T), RS1000390597 (14:31140472 G>A), RS1000404234 (14:31172209 C>A,T), RS1000414459 (14:31146628 C>A,G)

Disease associations

OMIM: gene MIM:618649 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Moderate	Autosomal dominant
neural tube defect	Limited	Autosomal dominant

Mondo (3): intellectual disability (MONDO:0001071), neurodevelopmental disorder (MONDO:0700092), neural tube defect (MONDO:0018075)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009436	Neural Tube Defects	C10.500.680; C16.131.666.680
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, decreases expression	3
trichostatin A	decreases expression, affects expression, affects cotreatment	3
Valproic Acid	decreases expression, increases methylation	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	2
Benzo(a)pyrene	decreases expression	2
FR900359	affects phosphorylation	1
geldanamycin	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
nobiletin	decreases reaction, increases expression	1
sodium arsenate	decreases reaction, increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
torcetrapib	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	increases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1
Caffeine	increases phosphorylation	1
Succimer	increases expression, affects cotreatment	1
Furaldehyde	affects cotreatment, decreases expression, affects localization, increases expression	1
Ivermectin	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B5K8	HAP1 HECTD1 (-) 2	Cancer cell line	Male
CVCL_XP50	HAP1 HECTD1 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

402 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02230072	PHASE1	COMPLETED	Fetoscopic Meningomyelocele Repair Study
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00060606	Not specified	COMPLETED	Management of Myelomeningocele Study (MOMS)
NCT00966927	Not specified	ACTIVE_NOT_RECRUITING	Assessment of Functional Independence and Quality of Life in Adolescents With Spina Bifid
NCT00975338	Not specified	COMPLETED	The LETS Study: A Longitudinal Evaluation of Transition Services
NCT02592291	Not specified	RECRUITING	Mobile Health Self-Management and Support System for Chronic and Complex Health Conditions
NCT03044821	Not specified	TERMINATED	Open Myelomeningocele Repair With High Maternal BMI
NCT03090633	Not specified	ACTIVE_NOT_RECRUITING	Fetoscopic Repair of Isolated Fetal Spina Bifida
NCT03544970	Not specified	COMPLETED	An Audit of the Posterior Fossa Characterization in Open Spina Bifida Based on Tertiary Center Experience
NCT04763382	Not specified	UNKNOWN	The Effect of Nursing Interventions for Clean Intermittent Catheterization Caregivers and Child
NCT05718440	Not specified	RECRUITING	Uronephrological Complications Risk Factors in Spinal Dysraphism
NCT05962086	Not specified	UNKNOWN	Determining Developmental and Clinical Markers Affecting Urinary Function of Children With Spinal Dysraphism
NCT06907732	Not specified	NOT_YET_RECRUITING	Fetoscopic Robotic Open Spina Bifida Treatment
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior