HECW2

Summary

HECW2 (HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2, HGNC:29853) is a protein-coding gene on chromosome 2q32.3, encoding E3 ubiquitin-protein ligase HECW2 (Q9P2P5). E3 ubiquitin-protein ligase that mediates ubiquitination of TP73.

This gene encodes a member of a family of E3 ubiquitin ligases which plays an important role in the proliferation, migration and differentiation of neural crest cells as a regulator of glial cell line-derived neurotrophic factor (GDNF)/Ret signaling. This gene also plays an important role in angiogenesis through stabilization of endothelial cell-to-cell junctions as a regulator of angiomotin-like 1 stability. The encoded protein contains an N-terminal calcium/lipid-binding (C2) domain involved in membrane targeting, two-four WW domains responsible for cellular localization and substrate recognition, and a C-terminal homologous with E6-associated protein C-terminus (HECT) catalytic domain. Naturally occurring mutations in this gene are associated with neurodevelopmental delay, hypotonia, and epilepsy. The decreased expression of this gene in the aganglionic colon is associated with Hirschsprung’s disease. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 57520 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 552 total — 8 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 40
• MANE Select transcript: NM_001348768

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29853
Approved symbol	HECW2
Name	HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2
Location	2q32.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1301, NEDL2
Ensembl gene	ENSG00000138411
Ensembl biotype	protein_coding
OMIM	617245
Entrez	57520

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 10 protein_coding, 6 retained_intron, 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000260983, ENST00000427457, ENST00000462290, ENST00000498146, ENST00000642318, ENST00000642531, ENST00000642884, ENST00000644030, ENST00000644256, ENST00000644405, ENST00000644421, ENST00000644978, ENST00000645468, ENST00000645770, ENST00000647236, ENST00000647314, ENST00000647402, ENST00000867916, ENST00000931760, ENST00000956007, ENST00000956008

RefSeq mRNA: 3 — MANE Select: NM_001348768 NM_001304840, NM_001348768, NM_020760

CCDS: CCDS33354

Canonical transcript exons

ENST00000644978 — 29 exons

Exon	Start	End
ENSE00000784084	196215865	196215977
ENSE00000784085	196217008	196217093
ENSE00000784086	196220039	196220153
ENSE00000784087	196220795	196220941
ENSE00000784089	196228102	196228254
ENSE00000934509	196240449	196240562
ENSE00001005034	196320339	196320439
ENSE00001005036	196306488	196306612
ENSE00001005038	196257823	196257906
ENSE00001005039	196317274	196317369
ENSE00001005042	196324980	196325149
ENSE00001005043	196222211	196222340
ENSE00001005044	196307935	196308085
ENSE00001005045	196225772	196225870
ENSE00001005047	196307130	196307233
ENSE00001005051	196292565	196292750
ENSE00001005057	196253920	196254029
ENSE00001005058	196242084	196242204
ENSE00001005061	196278528	196278662
ENSE00001165479	196433132	196433458
ENSE00001797519	196593508	196593554
ENSE00003505678	196271193	196271289
ENSE00003583583	196274021	196274123
ENSE00003586825	196322478	196322620
ENSE00003619342	196334424	196334518
ENSE00003659863	196318552	196319904
ENSE00003666768	196329575	196329650
ENSE00003705989	196194072	196201388
ENSE00003791009	196343657	196343764

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 91.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.1304 / max 234.9217, expressed in 1147 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
33037	1.2042	392
33013	0.9880	290
33034	0.9307	315
33038	0.8864	409
33017	0.8658	190
33018	0.7647	188
33012	0.6879	263
33039	0.6472	318
33040	0.4727	250
33011	0.4026	209

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	91.43	gold quality
Brodmann (1909) area 23	UBERON:0013554	89.64	gold quality
middle temporal gyrus	UBERON:0002771	88.91	gold quality
visceral pleura	UBERON:0002401	86.89	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.80	gold quality
adrenal tissue	UBERON:0018303	86.46	gold quality
lung	UBERON:0002048	86.14	gold quality
upper lobe of lung	UBERON:0008948	85.74	gold quality
right lung	UBERON:0002167	85.56	gold quality
upper lobe of left lung	UBERON:0008952	85.56	gold quality
myocardium	UBERON:0002349	85.34	silver quality
primary visual cortex	UBERON:0002436	85.17	gold quality
Brodmann (1909) area 46	UBERON:0006483	84.95	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.75	gold quality
corpus callosum	UBERON:0002336	84.10	gold quality
lower lobe of lung	UBERON:0008949	83.73	gold quality
occipital lobe	UBERON:0002021	83.06	gold quality
secondary oocyte	CL:0000655	82.35	gold quality
endothelial cell	CL:0000115	81.90	gold quality
parietal pleura	UBERON:0002400	81.03	gold quality
cortical plate	UBERON:0005343	80.72	gold quality
apex of heart	UBERON:0002098	80.50	gold quality
heart left ventricle	UBERON:0002084	80.44	gold quality
cardiac ventricle	UBERON:0002082	80.37	gold quality
heart right ventricle	UBERON:0002080	80.36	gold quality
cerebellar vermis	UBERON:0004720	80.17	silver quality
buccal mucosa cell	CL:0002336	80.00	silver quality
prefrontal cortex	UBERON:0000451	79.66	gold quality
ventricular zone	UBERON:0003053	79.21	gold quality
esophagus squamous epithelium	UBERON:0006920	79.20	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	24.67
E-HCAD-9	yes	16.53
E-ANND-3	yes	11.97

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

193 targeting HECW2, 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-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-12136	99.98	72.81	5713

Literature-anchored findings (GeneRIF, showing 12)

• NEDL2 is a novel substrate of APC/C-Cdh1 as cells exit mitosis and functions as a regulator of the metaphase to anaphase transition (PMID:24163370)
• Low HECW2 expression is associated with cervical cancer. (PMID:25156441)
• This work lends further support to previously identified candidate gene HECW2 as a novel candidate gene in intellectual disability and epilepsy. In 39 patient-parent trios, 29 de novo mutations in coding sequence were identified. (PMID:27334371)
• HECW2 is an ubiquitin ligase that stabilises p73, a crucial mediator of neurodevelopment and neurogenesis. This study implicates pathogenic genetic variants in HECW2 as potential causes of neurodevelopmental disorders in humans. (PMID:27389779)
• HECW2, a novel EC ubiquitin E3 ligase, plays a critical role in stabilizing endothelial cell-to-cell junctions by regulating AMOT-like 1 (AMOTL1) stability. (PMID:27498087)
• Results show that HECW2 interacts with two lamin A-binding proteins: proliferating cell nuclear antigen (PCNA), via a canonical PCNA-interacting protein (PIP) motif, and lamin B1. HECW2 mediates their ubiquitination and targets them for proteasomal degradation. (PMID:29753763)
• Ectopic expression of HECW2 causes the ubiquitination of HP1alpha and beta, thereby targeting them for proteasomal degradation. (PMID:30208514)
• Association of HECW2 variants with developmental and epileptic encephalopathy and knockdown of zebrafish hecw2a. (PMID:33205896)
• HECW2-related disorder in four Japanese patients. (PMID:34047014)
• Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders. (PMID:34321324)
• A novel likely pathogenic heterozygous HECW2 missense variant in a family with variable expressivity of neurodevelopmental delay, hypotonia, and epileptiform EEG patterns. (PMID:34327820)
• Circ_0057583 facilitates brain microvascular endothelial cell injury through modulating miR-204-5p/NR4A1 axis. (PMID:34767155)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hecw2a	ENSDARG00000062447
danio_rerio	hecw2b	ENSDARG00000063253
danio_rerio		ENSDARG00000113848
mus_musculus	Hecw2	ENSMUSG00000042807
rattus_norvegicus	Hecw2	ENSRNOG00000013257

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), 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 HECW2 — Q9P2P5 (reviewed: Q9P2P5)

Alternative names: HECT, C2 and WW domain-containing protein 2, HECT-type E3 ubiquitin transferase HECW2, NEDD4-like E3 ubiquitin-protein ligase 2

All UniProt accessions (4): Q9P2P5, A0A2R8Y6F3, A0A2R8YE75, C9JHL2

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that mediates ubiquitination of TP73. Acts to stabilize TP73 and enhance activation of transcription by TP73. Involved in the regulation of mitotic metaphase/anaphase transition.

Subunit / interactions. Interacts with TP73. Interacts with FZR1.

Subcellular location. Cytoplasm. Cytoskeleton. Spindle.

Tissue specificity. Predominantly expressed in adult brain, lung and heart.

Post-translational modifications. Ubiquitinated and degraded during mitotic exit by APC/C-Cdh1.

Disease relevance. Neurodevelopmental disorder with hypotonia, seizures, and absent language (NDHSAL) [MIM:617268] A neurodevelopmental disorder characterized by severely delayed psychomotor development, absent speech, epilepsy, encephalopathy, hypotonia, dystonia/dyskinesia, and macrocephaly. Brain imaging show cerebral atrophy, enlarged ventricles, and white matter abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9P2P5-1	1	yes
Q9P2P5-2	2

RefSeq proteins (3): NP_001291769, NP_001335697, NP_065811 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR000569	HECT_dom	Domain
IPR001202	WW_dom	Domain
IPR032348	HECW_N	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR035983	Hect_E3_ubiquitin_ligase	Homologous_superfamily
IPR036020	WW_dom_sf	Homologous_superfamily
IPR037795	C2_HECW	Domain
IPR040524	HECW1_helix	Domain
IPR050409	E3_ubiq-protein_ligase	Family

Pfam: PF00168, PF00397, PF00632, PF16562, PF18436

UniProt features (42 total): compositionally biased region 9, strand 8, region of interest 5, domain 4, modified residue 4, sequence variant 4, splice variant 3, chain 1, coiled-coil region 1, active site 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2LFE	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P2P5-F1	62.07	0.23

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): 1540 (glycyl thioester intermediate)

Post-translational modifications (4): 48, 852, 909, 1175

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 272 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_CHROMOSOME_ORGANIZATION, TAATAAT_MIR126, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_REGULATION_OF_DENDRITE_MORPHOGENESIS, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, CCATCCA_MIR432, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_REGULATION_OF_CHROMOSOME_SEGREGATION, GOBP_DENDRITE_MORPHOGENESIS

GO Biological Process (4): ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), regulation of mitotic metaphase/anaphase transition (GO:0030071), regulation of dendrite morphogenesis (GO:0048814)

GO Molecular Function (4): ubiquitin protein ligase activity (GO:0061630), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (4): cytoplasm (GO:0005737), mitotic spindle (GO:0072686), spindle (GO:0005819), cytoskeleton (GO:0005856)

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
intracellular membraneless organelle	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
protein modification by small protein conjugation	1
metaphase/anaphase transition of mitotic cell cycle	1
regulation of mitotic cell cycle phase transition	1
regulation of metaphase/anaphase transition of cell cycle	1
regulation of anatomical structure morphogenesis	1
dendrite morphogenesis	1
regulation of dendrite development	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein transferase activity	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
cellular anatomical structure	1
spindle	1
microtubule cytoskeleton	1

Protein interactions and networks

STRING

1713 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HECW2	AMOTL1	Q8IY63	627
HECW2	NEDD8	Q15843	559
HECW2	DISP3	Q9P2K9	444
HECW2	STK17B	O94768	437
HECW2	SUMO2	P55855	437
HECW2	SART3	Q15020	429
HECW2	UBE2O	Q9C0C9	427
HECW2	EMC7	Q9NPA0	423
HECW2	PCNP	Q8WW12	416
HECW2	TULP4	Q9NRJ4	413
HECW2	JUN	P05412	409
HECW2	MEPCE	Q7L2J0	407
HECW2	LARP7	Q4G0J3	402
HECW2	TMOD2	Q9NZR1	401
HECW2	BAZ1A	Q9NRL2	397

IntAct

54 interactions, top by confidence:

A	B	Type	Score
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
ARRDC1	WWP2	psi-mi:“MI:0914”(association)	0.850
ARRDC3	WWP2	psi-mi:“MI:0914”(association)	0.770
LDLRAD4	NEDD4	psi-mi:“MI:0914”(association)	0.690
HECW2	ENTREP1	psi-mi:“MI:0915”(physical association)	0.660
SPART	ITCH	psi-mi:“MI:0914”(association)	0.640
ARRDC1	NEDD4	psi-mi:“MI:0914”(association)	0.640
MS4A10	NEDD4	psi-mi:“MI:0914”(association)	0.590
TMEM51	WWP2	psi-mi:“MI:0914”(association)	0.530
LDLRAD4	WWP2	psi-mi:“MI:0914”(association)	0.530
WBP1	EXTL3	psi-mi:“MI:0914”(association)	0.530
ENTREP3	NEDD4	psi-mi:“MI:0914”(association)	0.530
CUEDC1	TOM1	psi-mi:“MI:0914”(association)	0.530
DVL2	WWP2	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
HECW2	HNRNPD	psi-mi:“MI:0915”(physical association)	0.400
FBXL15	HECW2	psi-mi:“MI:0915”(physical association)	0.400
FAM189B	KLRG2	psi-mi:“MI:0914”(association)	0.350
LDLRAD4	WWP2	psi-mi:“MI:0914”(association)	0.350

BioGRID (360): UBE2D3 (Reconstituted Complex), UBE2L3 (Reconstituted Complex), HECW2 (Biochemical Activity), HECW2 (Affinity Capture-MS), HECW2 (Affinity Capture-MS), HECW2 (Affinity Capture-MS), HECW2 (Affinity Capture-MS), HECW2 (Affinity Capture-MS), HECW2 (Affinity Capture-MS), HECW2 (Biochemical Activity), UBE2L3 (Reconstituted Complex), HECW2 (Affinity Capture-MS), HECW2 (Affinity Capture-MS), HECW2 (Affinity Capture-MS), HECW2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GTS1, A0A1B0GWH4, A1A4L6, A1YGI6, A6NDR6, B8QB46, F1MJR8, F1QDF8, O35892, O35893, P09015, P15036, P15037, P23497, P52729, P59598, Q32NH9, Q3KRF1, Q3UM89, Q4G112, Q4V7E1, Q5M7N6, Q5ND04, Q5XIV2, Q5ZHX5, Q66IG8, Q6P1R3, Q6PCX9, Q6PJQ5, Q708W2, Q76I76, Q76I79, Q76N89, Q7M6U3, Q8AXQ4, Q8BVK9, Q8IUE0, Q8IUE1, Q8IWB6, Q8IXJ9

Diamond homologs: A0A8C0NGY6, A1CQG2, A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B8N7E5, D3ZBM7, D6C652, E1B7Q7, E1C656, F1LP64, F1N6G5, F8W2M1, G0S9J5, G5E870, H2LBU8, O00308, O08759, O13834, O14326, O15033, P39940, P40985, P46934, P46935, P46937, P46938, P51593, P53119, Q03280, Q05086, Q08CZ0, Q09291, Q0CCL1, Q14669, Q15034, Q15386, Q1K9C4

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
HECW2	“up-regulates activity”	PI3K	binding
HECW2	“up-regulates activity”	AKT	binding
Ub:E2	“up-regulates activity”	HECW2	ubiquitination
HECW2	“up-regulates activity”	AMOTL1	ubiquitination
HECW2	“up-regulates quantity by stabilization”	TP73	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	27
Uncertain significance	311
Likely benign	119
Benign	27

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012237	NM_001348768.2(HECW2):c.4331G>C (p.Arg1444Thr)	Pathogenic
1027614	NM_001348768.2(HECW2):c.4333G>C (p.Glu1445Gln)	Pathogenic
1327493	NM_001348768.2(HECW2):c.736C>T (p.Arg246Ter)	Pathogenic
242317	NM_001348768.2(HECW2):c.3572G>A (p.Arg1191Gln)	Pathogenic
242318	NM_001348768.2(HECW2):c.3988C>T (p.Arg1330Trp)	Pathogenic
242324	NM_001348768.2(HECW2):c.3577T>G (p.Phe1193Val)	Pathogenic
4072353	NM_001348768.2(HECW2):c.3601dup (p.Tyr1201fs)	Pathogenic
984978	NM_001348768.2(HECW2):c.3587A>G (p.Lys1196Arg)	Pathogenic
1027607	NM_001348768.2(HECW2):c.412A>G (p.Ile138Val)	Likely pathogenic
1027609	NM_001348768.2(HECW2):c.2587T>C (p.Tyr863His)	Likely pathogenic
1027613	NM_001348768.2(HECW2):c.4323T>G (p.Phe1441Leu)	Likely pathogenic
1027615	NM_001348768.2(HECW2):c.4355G>T (p.Gly1452Val)	Likely pathogenic
1027616	NM_001348768.2(HECW2):c.4507A>G (p.Thr1503Ala)	Likely pathogenic
1320205	NM_001348768.2(HECW2):c.4343T>C (p.Leu1448Ser)	Likely pathogenic
1806140	NM_001348768.2(HECW2):c.4510T>G (p.Ser1504Ala)	Likely pathogenic
2441886	NM_001348768.2(HECW2):c.811C>T (p.Arg271Cys)	Likely pathogenic
2651780	NM_001348768.2(HECW2):c.4355G>C (p.Gly1452Ala)	Likely pathogenic
3364637	NM_001348768.2(HECW2):c.3596A>G (p.Asn1199Ser)	Likely pathogenic
3384051	NM_001348768.2(HECW2):c.4048G>T (p.Asp1350Tyr)	Likely pathogenic
3776297	NM_001348768.2(HECW2):c.4690G>A (p.Glu1564Lys)	Likely pathogenic
391956	NM_001348768.2(HECW2):c.2581C>T (p.Arg861Trp)	Likely pathogenic
4277400	NM_001348768.2(HECW2):c.2695C>T (p.Arg899Ter)	Likely pathogenic
4528905	NM_001348768.2(HECW2):c.4543C>T (p.Arg1515Ter)	Likely pathogenic
521049	NM_001348768.2(HECW2):c.3583G>C (p.Ala1195Pro)	Likely pathogenic
522012	NM_001348768.2(HECW2):c.3989G>A (p.Arg1330Gln)	Likely pathogenic
522028	NM_001348768.2(HECW2):c.4714G>A (p.Glu1572Lys)	Likely pathogenic
545253	NC_000002.12:g.(?196588283)(196600831_?)del	Likely pathogenic
666587	NM_001348768.2(HECW2):c.4471G>C (p.Glu1491Gln)	Likely pathogenic
801845	NM_001348768.2(HECW2):c.4343T>G (p.Leu1448Trp)	Likely pathogenic
807428	NM_001348768.2(HECW2):c.4321T>C (p.Phe1441Leu)	Likely pathogenic

SpliceAI

6283 predictions. Top by Δscore:

Variant	Effect	Δscore
2:196215976:AA:A	acceptor_gain	1.0000
2:196215978:C:CC	acceptor_gain	1.0000
2:196215978:C:CG	acceptor_loss	1.0000
2:196215979:T:C	acceptor_loss	1.0000
2:196215987:C:CT	acceptor_gain	1.0000
2:196215987:C:T	acceptor_gain	1.0000
2:196215988:A:T	acceptor_gain	1.0000
2:196217002:TCTCA:T	donor_loss	1.0000
2:196217003:CTCAC:C	donor_loss	1.0000
2:196217004:TCACC:T	donor_loss	1.0000
2:196217005:CA:C	donor_loss	1.0000
2:196217006:A:AT	donor_loss	1.0000
2:196217007:C:A	donor_loss	1.0000
2:196220037:ACCT:A	donor_gain	1.0000
2:196220038:CCTC:C	donor_gain	1.0000
2:196220040:T:TA	donor_gain	1.0000
2:196220074:A:AC	donor_gain	1.0000
2:196220074:AGGT:A	donor_gain	1.0000
2:196220075:G:C	donor_gain	1.0000
2:196220151:CACCT:C	acceptor_loss	1.0000
2:196220154:C:A	acceptor_loss	1.0000
2:196220155:T:A	acceptor_loss	1.0000
2:196220791:TTAC:T	donor_loss	1.0000
2:196220792:TAC:T	donor_loss	1.0000
2:196220793:AC:A	donor_loss	1.0000
2:196220794:C:CG	donor_loss	1.0000
2:196220816:G:C	donor_gain	1.0000
2:196220938:TTATC:T	acceptor_loss	1.0000
2:196220939:TATC:T	acceptor_loss	1.0000
2:196220940:ATCT:A	acceptor_loss	1.0000

AlphaMissense

10374 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:196201289:A:C	F1569L	1.000
2:196201289:A:T	F1569L	1.000
2:196201291:A:G	F1569L	1.000
2:196201308:A:T	V1563D	1.000
2:196201320:A:G	L1559P	1.000
2:196201332:A:G	L1555P	1.000
2:196201332:A:T	L1555H	1.000
2:196201351:A:C	Y1549D	1.000
2:196201356:G:C	P1547R	1.000
2:196201356:G:T	P1547H	1.000
2:196201359:A:C	L1546R	1.000
2:196201359:A:G	L1546P	1.000
2:196201359:A:T	L1546Q	1.000
2:196201363:C:G	D1545H	1.000
2:196201365:A:C	L1544R	1.000
2:196201365:A:G	L1544P	1.000
2:196201365:A:T	L1544Q	1.000
2:196201368:C:G	R1543P	1.000
2:196201369:G:C	R1543G	1.000
2:196201369:G:T	R1543S	1.000
2:196201370:G:C	N1542K	1.000
2:196201370:G:T	N1542K	1.000
2:196201373:A:C	F1541L	1.000
2:196201373:A:T	F1541L	1.000
2:196201374:A:C	F1541C	1.000
2:196201374:A:G	F1541S	1.000
2:196201375:A:G	F1541L	1.000
2:196201375:A:T	F1541I	1.000
2:196201376:A:C	C1540W	1.000
2:196201377:C:T	C1540Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000011321 (2:196230896 G>A,C), RS1000014998 (2:196270751 A>C), RS1000044681 (2:196313292 C>G,T), RS1000057143 (2:196520133 G>A), RS1000061066 (2:196512122 G>C), RS1000065162 (2:196360869 C>CAA), RS1000070155 (2:196483354 T>C), RS1000096188 (2:196282522 T>G), RS1000096882 (2:196422313 G>A), RS1000100659 (2:196560547 T>C,G), RS1000104256 (2:196279318 G>T), RS1000105087 (2:196255851 T>C), RS1000109448 (2:196575941 C>T), RS1000111794 (2:196212935 A>G), RS1000120855 (2:196449931 A>C)

Disease associations

OMIM: gene MIM:617245 | disease phenotypes: MIM:617268, MIM:617527, MIM:157900, MIM:181500, MIM:162200

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with hypotonia, seizures, and absent language	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD
complex neurodevelopmental disorder	Moderate	AR

Mondo (8): neurodevelopmental disorder with hypotonia, seizures, and absent language (MONDO:0014995), congenital nervous system disorder (MONDO:0002320), neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (MONDO:0060502), Mobius syndrome (MONDO:0008006), intellectual disability (MONDO:0001071), complex neurodevelopmental disorder (MONDO:0100038), schizophrenia (MONDO:0005090), neurofibromatosis type 1 (MONDO:0018975)

Orphanet (6): PLAA-associated neurodevelopmental disorder (Orphanet:521426), Moebius syndrome (Orphanet:570), Non-specific syndromic intellectual disability (Orphanet:528084), Neurofibromatosis type 1 (Orphanet:636), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000154	Wide mouth
HP:0000179	Thick lower lip vermilion
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000400	Macrotia
HP:0000414	Bulbous nose
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000506	Telecanthus
HP:0000508	Ptosis
HP:0000574	Thick eyebrow
HP:0000639	Nystagmus
HP:0000729	Autistic behavior
HP:0000938	Osteopenia
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0002059	Cerebral atrophy
HP:0002119	Ventriculomegaly
HP:0002197	Generalized-onset seizure
HP:0002353	EEG abnormality
HP:0002500	Abnormal cerebral white matter morphology
HP:0002705	High, narrow palate

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003486_4	Response to fenofibrate (LDL cholesterol levels)	1.000000e-07
GCST006979_76	Heel bone mineral density	5.000000e-12
GCST006979_77	Heel bone mineral density	1.000000e-14
GCST008156_141	Hip circumference adjusted for BMI	8.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007804	LDL cholesterol change measurement
EFO:0009270	heel bone mineral density
EFO:0008039	BMI-adjusted hip circumference

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
D020331	Mobius Syndrome	C07.465.299.825; C10.292.319.825; C10.292.562.700.375.750; C11.590.436.400.750; C16.131.077.578; C16.614.595
D009456	Neurofibromatosis 1	C04.557.580.600.580.590.650; C04.700.631.650; C10.562.600.500; C10.574.500.549.400; C10.668.829.675; C16.320.400.560.400; C16.320.700.633.650

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
Valproic Acid	affects expression, decreases expression	4
Benzo(a)pyrene	affects methylation, increases methylation	2
Estradiol	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
sotorasib	affects cotreatment, increases expression	1
TL8-506	affects cotreatment, increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	increases reaction, affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
clothianidin	decreases expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression, affects cotreatment	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia