HECTD4

Summary

HECTD4 (HECT domain E3 ubiquitin protein ligase 4, HGNC:26611) is a protein-coding gene on chromosome 12q24.13, encoding Probable E3 ubiquitin-protein ligase HECTD4 (Q9Y4D8). 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.

Predicted to enable ubiquitin-protein transferase activity. Involved in glucose homeostasis and glucose metabolic process. Predicted to be located in membrane.

Source: NCBI Gene 283450 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum (Strong, GenCC)
• GWAS associations: 73
• Clinical variants (ClinVar): 585 total — 7 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 53
• MANE Select transcript: NM_001388303

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26611
Approved symbol	HECTD4
Name	HECT domain E3 ubiquitin protein ligase 4
Location	12q24.13
Locus type	gene with protein product
Status	Approved
Aliases	FLJ34154, KIAA0614
Ensembl gene	ENSG00000173064
Ensembl biotype	protein_coding
OMIM	620209
Entrez	283450

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 7 retained_intron, 4 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000311694, ENST00000377560, ENST00000547085, ENST00000547352, ENST00000547519, ENST00000548140, ENST00000548588, ENST00000548896, ENST00000549141, ENST00000549306, ENST00000550722, ENST00000550724, ENST00000550968, ENST00000552437, ENST00000651701, ENST00000682272

RefSeq mRNA: 2 — MANE Select: NM_001388303 NM_001109662, NM_001388303

CCDS: CCDS91751

Canonical transcript exons

ENST00000682272 — 76 exons

Exon	Start	End
ENSE00001474316	112163042	112163264
ENSE00001474338	112203636	112203772
ENSE00001474362	112228647	112228811
ENSE00001474364	112230687	112230822
ENSE00001474365	112231513	112231715
ENSE00001474367	112233004	112233085
ENSE00001474368	112235077	112235266
ENSE00001474369	112235504	112235784
ENSE00001474370	112236945	112237098
ENSE00001474371	112239052	112239236
ENSE00001474373	112239881	112240027
ENSE00001474374	112243353	112243519
ENSE00001474376	112243620	112243761
ENSE00001474377	112243874	112244009
ENSE00001474379	112246901	112247076
ENSE00001474381	112247462	112247550
ENSE00001549850	112169503	112169658
ENSE00001550231	112273655	112273795
ENSE00001550803	112279228	112279386
ENSE00001552286	112250144	112250377
ENSE00001552311	112193469	112193674
ENSE00001553029	112190786	112190965
ENSE00001554418	112179174	112179397
ENSE00001554579	112194885	112195066
ENSE00001555630	112170333	112170452
ENSE00001556084	112248320	112248512
ENSE00001557801	112178931	112179082
ENSE00001559666	112283110	112283302
ENSE00001560614	112184187	112185493
ENSE00001561073	112192560	112192765
ENSE00001562458	112193061	112193191
ENSE00001564018	112171117	112171263
ENSE00001564355	112248067	112248171
ENSE00001564654	112183059	112183266
ENSE00001687466	112274847	112274960
ENSE00003467012	112265878	112265983
ENSE00003477377	112306064	112306234
ENSE00003499143	112208494	112208630
ENSE00003505344	112163542	112163737
ENSE00003510634	112259112	112259265
ENSE00003516688	112264084	112264212
ENSE00003519334	112226643	112226758
ENSE00003523336	112167814	112167917
ENSE00003534061	112270227	112270459
ENSE00003534269	112217034	112217195
ENSE00003537727	112313017	112313147
ENSE00003542095	112216773	112216921
ENSE00003552824	112212487	112212650
ENSE00003558676	112164109	112164275
ENSE00003561686	112210015	112210252
ENSE00003568641	112229698	112229880
ENSE00003573773	112314457	112314546
ENSE00003584074	112252424	112252528
ENSE00003584749	112200638	112200798
ENSE00003585405	112167317	112167538
ENSE00003587889	112266912	112266982
ENSE00003592727	112216292	112216371
ENSE00003610141	112228089	112228258
ENSE00003633704	112250971	112251134
ENSE00003634274	112265175	112265295
ENSE00003636373	112258496	112258596
ENSE00003642059	112207874	112208000
ENSE00003644803	112309561	112309669
ENSE00003645244	112269704	112269849
ENSE00003648753	112204486	112204623
ENSE00003666206	112254043	112254162
ENSE00003672144	112256320	112256518
ENSE00003687047	112261305	112261429
ENSE00003691855	112219386	112219489
ENSE00003692991	112308753	112308891
ENSE00003707123	112175736	112175859
ENSE00003707594	112176596	112176702
ENSE00003707740	112172671	112172861
ENSE00003775855	112319225	112319742
ENSE00003916165	112160195	112162523
ENSE00003918674	112381952	112382431

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.3511 / max 276.9232, expressed in 1803 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133329	10.6192	1783
133328	4.7319	1472

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	98.01	gold quality
cerebellar cortex	UBERON:0002129	97.84	gold quality
cerebellar hemisphere	UBERON:0002245	97.84	gold quality
cerebellum	UBERON:0002037	97.61	gold quality
middle temporal gyrus	UBERON:0002771	97.52	gold quality
cortical plate	UBERON:0005343	97.36	gold quality
ganglionic eminence	UBERON:0004023	97.10	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.50	gold quality
paraflocculus	UBERON:0005351	96.19	gold quality
cerebellar vermis	UBERON:0004720	96.02	gold quality
right frontal lobe	UBERON:0002810	95.81	gold quality
primary visual cortex	UBERON:0002436	95.62	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.95	gold quality
occipital lobe	UBERON:0002021	94.64	gold quality
prefrontal cortex	UBERON:0000451	94.58	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.55	gold quality
cingulate cortex	UBERON:0003027	94.49	gold quality
inferior olivary complex	UBERON:0002127	94.42	gold quality
anterior cingulate cortex	UBERON:0009835	94.41	gold quality
neocortex	UBERON:0001950	94.33	gold quality
lower esophagus mucosa	UBERON:0035834	94.33	gold quality
frontal cortex	UBERON:0001870	94.19	gold quality
brain	UBERON:0000955	94.18	gold quality
nucleus accumbens	UBERON:0001882	94.17	gold quality
central nervous system	UBERON:0001017	94.14	gold quality
cerebral cortex	UBERON:0000956	94.08	gold quality
orbitofrontal cortex	UBERON:0004167	94.01	gold quality
telencephalon	UBERON:0001893	93.88	gold quality
caudate nucleus	UBERON:0001873	93.79	gold quality
putamen	UBERON:0001874	93.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.15

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DOT1L, MYC

miRNA regulators (miRDB)

176 targeting HECTD4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-374A-5P	99.90	71.34	2923

Literature-anchored findings (GeneRIF, showing 6)

• Newly implicated variants (MYL2, C12orf51 and OAS1) were found to be significantly associated with 1-h plasma glucose as predisposing risk factors for type 2 diabetes. (PMID:23575436)
• There was no significant association between C12orf51 rs11066280 and survival of gastric cancer. (PMID:25661349)
• SNPs in the HECTD4 gene is associated with decreased thoracic-to-hip circumference ratio in male Koreans. (PMID:26675016)
• This exome-wide association study indicated that C12orf51 rs11066280, MYL2 rs12229654, and ALDH2 rs671 polymorphisms are linked to blood Pb levels in the Korean population. (PMID:28212632)
• A Genome-Wide Association Study of a Korean Population Identifies Genetic Susceptibility to Hypertension Based on Sex-Specific Differences. (PMID:34828409)
• Biallelic variants in HECT E3 paralogs, HECTD4 and UBE3C, encoding ubiquitin ligases cause neurodevelopmental disorders that overlap with Angelman syndrome. (PMID:36401616)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	HECTD4	ENSDARG00000101079
mus_musculus	Hectd4	ENSMUSG00000042744
rattus_norvegicus	Hectd4	ENSRNOG00000001352

Paralogs (24): HECW1 (ENSG00000002746), UBE3C (ENSG00000009335), NEDD4L (ENSG00000049759), NEDD4 (ENSG00000069869), ITCH (ENSG00000078747), HACE1 (ENSG00000085382), HUWE1 (ENSG00000086758), HECTD1 (ENSG00000092148), 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), WWP2 (ENSG00000198373), SMURF1 (ENSG00000198742)

Protein

Protein identifiers

Probable E3 ubiquitin-protein ligase HECTD4 — Q9Y4D8 (reviewed: Q9Y4D8)

Alternative names: HECT domain-containing protein 4, HECT-type E3 ubiquitin transferase HECTD4

All UniProt accessions (6): A0A494C150, A0A804HJX8, F8VU57, F8VWT9, J3KPF0, V9GYT9

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.

Subcellular location. Membrane.

Disease relevance. Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum (NEDSSCC) [MIM:620250] An autosomal recessive neurodevelopmental disorder characterized by global developmental delay, hypotonia, and seizures. Other features include peripheral spasticity with hyperreflexia, variable dysmorphic features, impaired intellectual development, behavioral abnormalities, and hypoplasia or absence of the corpus callosum on brain imaging. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9Y4D8-1	1	yes
Q9Y4D8-2	2
Q9Y4D8-3	3
Q9Y4D8-4	4
Q9Y4D8-5	5, POTAGE

RefSeq proteins (2): NP_001103132, NP_001375232* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000569	HECT_dom	Domain
IPR035781	SPRY_HECTD4	Domain
IPR035983	Hect_E3_ubiquitin_ligase	Homologous_superfamily
IPR043136	B30.2/SPRY_sf	Homologous_superfamily
IPR043366	HECTD4	Family

Pfam: PF00632

UniProt features (51 total): sequence conflict 19, splice variant 8, compositionally biased region 7, sequence variant 6, region of interest 6, chain 1, transmembrane region 1, active site 1, modified residue 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q9Y4D8 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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): 3964 (glycyl thioester intermediate)

Post-translational modifications (1): 2080

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 228 (showing top): IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, MODULE_206, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_GLUCOSE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_HOMEOSTASIS, AACTTT_UNKNOWN, LIU_CMYB_TARGETS_UP, GOBP_MONOSACCHARIDE_METABOLIC_PROCESS, LIU_VMYB_TARGETS_UP, AR_Q2, CP2_01, LIU_SOX4_TARGETS_DN, GOBP_HOMEOSTATIC_PROCESS, GOBP_CHEMICAL_HOMEOSTASIS

GO Biological Process (3): glucose metabolic process (GO:0006006), protein ubiquitination (GO:0016567), glucose homeostasis (GO:0042593)

GO Molecular Function (2): ubiquitin protein ligase activity (GO:0061630), ubiquitin-protein transferase activity (GO:0004842)

GO Cellular Component (1): membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
hexose metabolic process	1
protein modification by small protein conjugation	1
carbohydrate homeostasis	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein transferase activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

762 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HECTD4	CCDC63	Q8NA47	700
HECTD4	ALDH2	P05091	673
HECTD4	ACAD10	Q6JQN1	667
HECTD4	TMEM116	Q8NCL8	544
HECTD4	TTC32	Q5I0X7	487
HECTD4	NAA25	Q14CX7	480
HECTD4	EVC	P57679	462
HECTD4	SLC17A3	O00476	449
HECTD4	GGA3	Q9NZ52	424
HECTD4	MYL2	P10916	418
HECTD4	CDSN	Q15517	418
HECTD4	CUX2	O14529	398
HECTD4	TRAFD1	O14545	389
HECTD4	BRCA1	P38398	388
HECTD4	ERP29	P30040	383

IntAct

21 interactions, top by confidence:

A	B	Type	Score
SLC12A2	CLGN	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAZ	HECTD4	psi-mi:“MI:0915”(physical association)	0.560
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
CYLD	HECTD4	psi-mi:“MI:0407”(direct interaction)	0.440
HECTD4	H2BC20P	psi-mi:“MI:0915”(physical association)	0.400
HECTD4	INCENP	psi-mi:“MI:0915”(physical association)	0.400
NS1	SAC3D1	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
YWHAZ	SPEG	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
CSNK1G2	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
CEP192	WASL	psi-mi:“MI:0914”(association)	0.350
GPC3	PXDNL	psi-mi:“MI:0914”(association)	0.350
USP20	MYO9A	psi-mi:“MI:0914”(association)	0.350
YWHAG	RPSA2	psi-mi:“MI:2364”(proximity)	0.270

ESM2 similar proteins: A0A0R4I9Y1, A0A0R4IBK5, A2AN08, A2ARZ3, A5WUT8, A6NKT7, B1WBT0, B8RJM0, C9JQI7, E9Q3L2, E9Q555, H2QII6, O08662, O14715, O15050, O43310, O75592, O75969, P0DJD0, P0DJD1, P13864, P42356, P49792, Q0V9S3, Q0VF22, Q24K09, Q2TL32, Q4R6W9, Q4V847, Q63HN8, Q6PB60, Q6PEE2, Q71HP2, Q7TPH6, Q7TPV2, Q7Z3J3, Q80930, Q80TA9, Q810N5, Q811D2

Diamond homologs: A1CQG2, A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B8N7E5, D3ZBM7, E1C656, F1N6G5, F2Z461, F8W2M1, G0S9J5, O00308, O08759, O13834, O14326, O94275, O95071, P39940, P40985, P46934, P46935, P51592, P51593, Q03280, Q05086, Q0CCL1, Q15034, Q1K9C4, Q28BK1, Q2TAS2, Q2UBP1, Q3U0D9, Q4WTF3, Q5BDP1, Q5GLZ8, Q5PQN1, Q5RBF2, Q5RD78

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
MYC	“down-regulates quantity by repression”	HECTD4	“transcriptional regulation”
HECTD4	“down-regulates quantity by destabilization”	MYC	ubiquitination
HECTD4	“down-regulates quantity by destabilization”	AR	ubiquitination
DOT1L	“down-regulates quantity by repression”	HECTD4	“transcriptional regulation”
Ub:E2	“up-regulates activity”	HECTD4	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 29 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	5	223.9×	1e-09
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	197.6×	1e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	197.6×	1e-09
Activation of BH3-only proteins	5	146.0×	4e-09
RHO GTPases activate PKNs	5	93.3×	4e-08
Intrinsic Pathway for Apoptosis	5	86.1×	5e-08
SARS-CoV-1-host interactions	5	51.7×	5e-07
Apoptosis	5	49.4×	6e-07

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	5	23.8×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	4
Uncertain significance	452
Likely benign	39
Benign	6

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
2444471	NM_001388303.1(HECTD4):c.2230C>T (p.Arg744Ter)	Pathogenic
2444472	NM_001388303.1(HECTD4):c.4912del (p.Thr1638fs)	Pathogenic
2444473	NM_001388303.1(HECTD4):c.6794C>G (p.Thr2265Arg)	Pathogenic
2444474	NM_001388303.1(HECTD4):c.10219C>T (p.His3407Tyr)	Pathogenic
446245	NM_001388303.1(HECTD4):c.9985C>T (p.Gln3329Ter)	Pathogenic
59818	GRCh38/hg38 12q24.13(chr12:112303430-112676526)x3	Pathogenic
59819	GRCh38/hg38 12q24.13(chr12:112307532-112722967)x3	Pathogenic
1878507	NM_001388303.1(HECTD4):c.6367C>T (p.Gln2123Ter)	Likely pathogenic
2430068	NM_001388303.1(HECTD4):c.9724dup (p.Ala3242fs)	Likely pathogenic
2570658	NM_001388303.1(HECTD4):c.4958+1G>A	Likely pathogenic
3602605	NM_001388303.1(HECTD4):c.3989del (p.Val1330fs)	Likely pathogenic

SpliceAI

11875 predictions. Top by Δscore:

Variant	Effect	Δscore
12:112162523:CCTA:C	acceptor_loss	1.0000
12:112162525:T:G	acceptor_loss	1.0000
12:112163037:GGTAC:G	donor_loss	1.0000
12:112163039:TACC:T	donor_loss	1.0000
12:112163040:A:AT	donor_loss	1.0000
12:112163041:C:CG	donor_loss	1.0000
12:112163041:CCTG:C	donor_gain	1.0000
12:112163140:T:TA	donor_gain	1.0000
12:112163260:TGGGC:T	acceptor_gain	1.0000
12:112163261:GGGC:G	acceptor_gain	1.0000
12:112163262:GGC:G	acceptor_gain	1.0000
12:112163263:GC:G	acceptor_gain	1.0000
12:112163264:CC:C	acceptor_gain	1.0000
12:112163265:C:CC	acceptor_gain	1.0000
12:112163265:C:T	acceptor_gain	1.0000
12:112163537:TCTA:T	donor_loss	1.0000
12:112163538:CTAC:C	donor_loss	1.0000
12:112163539:TACCT:T	donor_loss	1.0000
12:112163540:ACCT:A	donor_loss	1.0000
12:112163733:CCCAC:C	acceptor_gain	1.0000
12:112163734:CCAC:C	acceptor_gain	1.0000
12:112163734:CCACC:C	acceptor_gain	1.0000
12:112163735:CAC:C	acceptor_gain	1.0000
12:112163735:CACC:C	acceptor_gain	1.0000
12:112163736:AC:A	acceptor_gain	1.0000
12:112163737:CC:C	acceptor_gain	1.0000
12:112163738:C:CC	acceptor_gain	1.0000
12:112163738:CT:C	acceptor_loss	1.0000
12:112163742:CCGGG:C	acceptor_gain	1.0000
12:112163743:C:T	acceptor_gain	1.0000

AlphaMissense

28776 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000001866 (12:112184511 G>A), RS1000008290 (12:112176356 T>G), RS1000012077 (12:112329373 T>G), RS1000069855 (12:112192695 C>T), RS1000080080 (12:112351880 C>A), RS1000089712 (12:112216165 G>C), RS1000101215 (12:112189911 G>A), RS1000102172 (12:112224334 C>T), RS1000124568 (12:112357119 A>C), RS1000138511 (12:112232431 A>G,T), RS1000148584 (12:112249251 G>A,T), RS1000149352 (12:112287507 C>G), RS1000183890 (12:112234698 A>T), RS1000209462 (12:112338579 C>T), RS1000213842 (12:112320313 G>A)

Disease associations

OMIM: gene MIM:620209 | disease phenotypes: MIM:620250

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum	Strong	Autosomal recessive

Mondo (2): neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum (MONDO:0859516), autism spectrum disorder (MONDO:0005258)

Orphanet (1): NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000154	Wide mouth
HP:0000160	Narrow mouth
HP:0000189	Narrow palate
HP:0000256	Macrocephaly
HP:0000275	Narrow face
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000400	Macrotia
HP:0000431	Wide nasal bridge
HP:0000470	Short neck
HP:0000494	Downslanted palpebral fissures
HP:0000520	Proptosis
HP:0000527	Long eyelashes
HP:0000582	Upslanted palpebral fissure
HP:0000592	Blue sclerae
HP:0000657	Oculomotor apraxia
HP:0000664	Synophrys
HP:0000668	Hypodontia
HP:0000685	Hypoplasia of teeth
HP:0000717	Autism
HP:0000718	Aggressive behavior
HP:0000739	Anxiety
HP:0001182	Tapered finger
HP:0001249	Intellectual disability

GWAS associations

73 associations (top):

Study	Trait	p-value
GCST000381_1	Biomedical quantitative traits	8.000000e-12
GCST000954_1	Alcohol consumption	9.000000e-59
GCST001089_1	Esophageal cancer	2.000000e-31
GCST001233_2	Metabolite levels	8.000000e-22
GCST001233_3	Metabolite levels	3.000000e-63
GCST001234_5	Gamma glutamyl transpeptidase	3.000000e-126
GCST001237_5	HDL cholesterol	7.000000e-37
GCST001474_12	Hypothyroidism	3.000000e-12
GCST001587_8	Coronary heart disease	2.000000e-11
GCST001610_9	Renal function-related traits (BUN)	2.000000e-09
GCST001842_1	Drinking behavior	3.000000e-215
GCST001845_2	Coronary heart disease	5.000000e-11
GCST001965_1	Glycemic traits	1.000000e-16
GCST001965_3	Glycemic traits	6.000000e-09
GCST001965_7	Glycemic traits	6.000000e-14
GCST002732_1	Metabolic syndrome	1.000000e-07
GCST003197_1	Thoracic-to-hip circumference ratio	6.000000e-09
GCST003679_14	C-reactive protein levels or LDL-cholesterol levels (pleiotropy)	8.000000e-09
GCST004232_33	HDL cholesterol levels	6.000000e-10
GCST004234_13	HDL cholesterol levels	4.000000e-09
GCST004404_6	Alcohol consumption (drinkers vs non-drinkers)	6.000000e-48
GCST004610_132	White blood cell count	7.000000e-10
GCST004613_34	Sum neutrophil eosinophil counts	2.000000e-10
GCST004614_12	Granulocyte count	2.000000e-10
GCST004620_82	Sum basophil neutrophil counts	2.000000e-09
GCST004626_120	Myeloid white cell count	1.000000e-09
GCST004629_132	Neutrophil count	1.000000e-09
GCST004904_168	Body mass index	1.000000e-08
GCST005329_1	Coffee consumption	2.000000e-16
GCST005330_2	Coffee consumption	2.000000e-15

EFO canonical traits (31, from GWAS)

EFO ID	Trait name
EFO:0004343	waist-hip ratio
EFO:0004329	alcohol drinking
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004315	drinking behavior
EFO:0000195	metabolic syndrome
EFO:0007769	thoracic-to-hip circumference ratio measurement
EFO:0004458	C-reactive protein measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007987	granulocyte count
EFO:0005090	basophil count
EFO:0004340	body mass index
EFO:0006782	cups of coffee per day measurement
EFO:0007835	alcohol dependence measurement
EFO:0006336	diastolic blood pressure
EFO:0006340	mean arterial pressure
EFO:0008393	reaction time measurement
EFO:0006335	systolic blood pressure
EFO:0004736	aspartate aminotransferase measurement
EFO:0004761	uric acid measurement
EFO:0004531	urate measurement
EFO:0007805	HDL cholesterol change measurement
EFO:0010139	fish consumption measurement
EFO:0004338	body weight
EFO:0010091	tea consumption measurement
EFO:0007986	reticulocyte count
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, affects cotreatment, decreases expression	2
Acetylcysteine	decreases reaction, increases expression, decreases expression	2
Benzo(a)pyrene	decreases expression	2
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	decreases expression, decreases reaction	1
coumarin	affects phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
eprenetapopt	affects expression, affects reaction	1
bisphenol S	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression	1
EPZ004777	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Ethanol	decreases reaction, increases expression, affects response to substance, decreases expression, increases reaction	1
Caffeine	affects phosphorylation	1
Calcium	affects abundance, affects reaction	1
Cisplatin	decreases expression	1
Demecolcine	increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Dinitrochlorobenzene	affects binding	1
Endosulfan	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Hydrogen Peroxide	increases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Lead	affects abundance, affects reaction	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder