UNC80

Summary

UNC80 (unc-80 subunit of NALCN channel complex, HGNC:26582) is a protein-coding gene on chromosome 2q34, encoding Protein unc-80 homolog (Q8N2C7). Auxiliary subunit of the NALCN sodium channel complex, a voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability.

The protein encoded by this gene is a component of a voltage-independent ’leak’ ion-channel complex, in which it performs essential functions, such as serving as a bridge between two other components (sodium leak channel non-selective and UNC79) and as a scaffold for Src kinases. Leak channels play an importnat role in establishment and maintenance of resting membrane potentials in neurons. Mutations in this gene are associated with congenital infantile encephalopathy, intellectual disability and growth issues.

Source: NCBI Gene 285175 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypotonia, infantile, with psychomotor retardation and characteristic facies 2 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 2,448 total — 74 pathogenic, 52 likely-pathogenic
• Phenotypes (HPO): 51
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001371986

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26582
Approved symbol	UNC80
Name	unc-80 subunit of NALCN channel complex
Location	2q34
Locus type	gene with protein product
Status	Approved
Aliases	FLJ33496, KIAA1843, UNC-80
Ensembl gene	ENSG00000144406
Ensembl biotype	protein_coding
OMIM	612636
Entrez	285175

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 5 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000272845, ENST00000333907, ENST00000439458, ENST00000477301, ENST00000477924, ENST00000478701, ENST00000481494, ENST00000489023, ENST00000673920, ENST00000673951, ENST00000715554

RefSeq mRNA: 3 — MANE Select: NM_001371986 NM_001371986, NM_032504, NM_182587

CCDS: CCDS2387, CCDS46504, CCDS92937

Canonical transcript exons

ENST00000673920 — 65 exons

Exon	Start	End
ENSE00001274987	209829232	209829379
ENSE00001609053	209817812	209817952
ENSE00001609460	209820311	209820679
ENSE00001620153	209818993	209819261
ENSE00001646329	209995329	209999296
ENSE00001665038	209816909	209817125
ENSE00001675323	209984856	209984912
ENSE00001720638	209825907	209826053
ENSE00001767785	209815257	209815391
ENSE00002240128	209813580	209813841
ENSE00003458428	209777258	209777559
ENSE00003461844	209773094	209773142
ENSE00003461871	209775889	209776045
ENSE00003466229	209972201	209972324
ENSE00003482491	209912560	209912667
ENSE00003486594	209922252	209922383
ENSE00003486978	209888095	209888260
ENSE00003493440	209834002	209834168
ENSE00003499013	209976913	209977078
ENSE00003504785	209877954	209878089
ENSE00003506006	209918532	209918663
ENSE00003513991	209970832	209970957
ENSE00003516638	209941221	209941489
ENSE00003518114	209834912	209835010
ENSE00003519628	209992166	209992247
ENSE00003520464	209935714	209935808
ENSE00003521606	209978529	209978708
ENSE00003525063	209786066	209786189
ENSE00003531519	209936844	209936933
ENSE00003541552	209793720	209793859
ENSE00003541758	209896313	209896413
ENSE00003542905	209945051	209945189
ENSE00003545814	209945847	209945943
ENSE00003549491	209937529	209937630
ENSE00003550271	209831443	209831591
ENSE00003553602	209976119	209976303
ENSE00003563785	209933822	209934005
ENSE00003576134	209993315	209993426
ENSE00003579703	209904765	209904965
ENSE00003584853	209921500	209921686
ENSE00003585537	209872758	209872970
ENSE00003588018	209917777	209917958
ENSE00003588816	209840542	209840648
ENSE00003604621	209842350	209842446
ENSE00003606113	209959119	209959154
ENSE00003611484	209959489	209959707
ENSE00003621229	209957644	209957736
ENSE00003624257	209954100	209954270
ENSE00003625304	209943380	209943514
ENSE00003628515	209967437	209967637
ENSE00003631236	209939472	209939652
ENSE00003636182	209929871	209929971
ENSE00003658181	209913802	209913940
ENSE00003664631	209969768	209969891
ENSE00003675298	209849451	209849623
ENSE00003677572	209930968	209931054
ENSE00003678774	209982179	209982317
ENSE00003680176	209973064	209973270
ENSE00003684111	209994065	209994264
ENSE00003686121	209926843	209926986
ENSE00003686806	209789532	209789605
ENSE00003692767	209880961	209881094
ENSE00003897952	209839222	209839430
ENSE00004027169	209894163	209894366
ENSE00004027189	209771832	209772164

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 95.80.

FANTOM5 (CAGE): breadth broad, TPM avg 2.7885 / max 203.6891, expressed in 211 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
24995	1.0096	167
24992	0.5205	148
24990	0.4672	107
24989	0.3291	100
24994	0.1598	73
24996	0.1565	79
24993	0.1070	56
24991	0.0388	23

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	95.80	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.73	gold quality
middle temporal gyrus	UBERON:0002771	94.12	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.65	gold quality
cerebellum	UBERON:0002037	90.36	gold quality
cerebellar cortex	UBERON:0002129	90.28	gold quality
cerebellar hemisphere	UBERON:0002245	90.21	gold quality
pons	UBERON:0000988	89.73	gold quality
endothelial cell	CL:0000115	89.02	gold quality
lateral nuclear group of thalamus	UBERON:0002736	88.10	gold quality
primary visual cortex	UBERON:0002436	87.85	gold quality
Brodmann (1909) area 46	UBERON:0006483	87.32	gold quality
occipital lobe	UBERON:0002021	86.30	gold quality
superior frontal gyrus	UBERON:0002661	85.46	gold quality
prefrontal cortex	UBERON:0000451	85.37	gold quality
frontal cortex	UBERON:0001870	84.78	gold quality
substantia nigra pars compacta	UBERON:0001965	84.47	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	83.74	gold quality
neocortex	UBERON:0001950	83.67	gold quality
pituitary gland	UBERON:0000007	83.64	gold quality
right frontal lobe	UBERON:0002810	83.44	gold quality
Brodmann (1909) area 9	UBERON:0013540	83.26	gold quality
superior vestibular nucleus	UBERON:0007227	83.23	gold quality
parietal lobe	UBERON:0001872	82.94	gold quality
entorhinal cortex	UBERON:0002728	82.91	gold quality
postcentral gyrus	UBERON:0002581	82.73	gold quality
cerebral cortex	UBERON:0000956	82.55	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.43	gold quality
adenohypophysis	UBERON:0002196	82.02	gold quality
brain	UBERON:0000955	81.88	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-75688	yes	190.98
E-HCAD-35	yes	57.90
E-MTAB-5061	yes	13.98
E-ANND-3	yes	7.18
E-GEOD-83139	yes	3.93
E-MTAB-6379	no	57.39
E-MTAB-6678	no	3.82

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

289 targeting UNC80, 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-8485	100.00	77.57	4731
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
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-548AW	99.99	72.57	3559
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 8)

• UNC80 functions as a scaffold for Src kinases in NALCN channel function. (PMID:19535918)
• UNC80 bridges between UNC79 and the cation channel NALCN. (PMID:26545877)
• findings demonstrate the fundamental significance of UNC80 and basal ionic conductance to human health (PMID:26708751)
• UNC80 encodes a large protein that is necessary for the stability and function of NALCN and for bridging NALCN to UNC79 to form a functional complex (PMID:26708753)
• Further supporting the UNC80 mutations as causative of these siblings’ disorder, biallelic mutations in UNC80 have recently been described among individuals with an overlapping phenotype. This report expands the disease spectrum associated with UNC80 mutations (PMID:27513830)
• Biallelic UNC80 mutations caused infantile hypotonia with psychomotor retardation and characteristic facies 2 in two Chinese patients with variable phenotypes (PMID:29572195)
• UNC80 variant is associated with neurodevelopmental diseases. (PMID:30167850)
• Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex. (PMID:32620897)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	unc80	ENSDARG00000098290
mus_musculus	Unc80	ENSMUSG00000055567
rattus_norvegicus	Unc80	ENSRNOG00000028362
drosophila_melanogaster	unc80	FBGN0039536
caenorhabditis_elegans		WBGENE00006812

Protein

Protein identifiers

Protein unc-80 homolog — Q8N2C7 (reviewed: Q8N2C7)

All UniProt accessions (5): Q8N2C7, A0A669KAW8, A0A669KBC5, A0AAQ5BIK4, H3BLU5

UniProt curated annotations — full annotation on UniProt →

Function. Auxiliary subunit of the NALCN sodium channel complex, a voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability. Activated by neuropeptides substance P, neurotensin, and extracellular Ca(2+) that regulates neuronal excitability by controlling the sizes of NALCN-dependent sodium-leak current. UNC80 is essential for NALCN sensitivity to extracellular Ca(2+).

Subunit / interactions. NALCN complex consists of NALCN and auxiliary subunits, UNC79, UNC80 and NACL1. These auxiliary subunits are essential for the NALCN complex function. Interacts (via N-terminus half) with NALCN; this interaction facilitates NALCN surface localization. Interacts with UNC79. UNC80 bridges NALCN to UNC79.

Subcellular location. Cell membrane.

Tissue specificity. Moderately expressed in fetal brain, spinal cord, skeletal muscle, thymus, spleen, fetal liver, small intestine, colon, kidney and uterus. Highly expressed in adrenal gland, prostate and testis, as well as in brain and cerebellum.

Post-translational modifications. Phosphorylated on tyrosine residues.

Disease relevance. Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 (IHPRF2) [MIM:616801] An autosomal recessive, neurodegenerative disease characterized by severe truncal hypotonia since birth or early infancy, progressive peripheral spasticity, and profound psychomotor developmental delay. Some patients may have seizures. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the unc-80 family.

Isoforms (7)

UniProt ID	Names	Canonical?
Q8N2C7-1	1	yes
Q8N2C7-2	2
Q8N2C7-3	3
Q8N2C7-4	4
Q8N2C7-5	5
Q8N2C7-6	6
Q8N2C7-7	7

RefSeq proteins (3): NP_001358915, NP_115893, NP_872393 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR031542	UNC80_N	Domain
IPR045852	UNC80_central	Domain
IPR046460	UNC80_C	Domain

Pfam: PF15778, PF19424, PF20262

UniProt features (169 total): helix 94, turn 16, compositionally biased region 14, region of interest 12, strand 10, splice variant 8, transmembrane region 4, sequence variant 4, modified residue 3, sequence conflict 3, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7SX3	ELECTRON MICROSCOPY	3.1
7SX4	ELECTRON MICROSCOPY	3.5
7WJI	ELECTRON MICROSCOPY	4.5

Predicted structure (AlphaFold)

No AlphaFold model available for Q8N2C7 — 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.

Post-translational modifications (3): 257, 525, 3042

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels

MSigDB gene sets: 291 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, RNGTGGGC_UNKNOWN, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, SP1_Q2_01, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_REGULATION_OF_ACTION_POTENTIAL, GOBP_REGULATION_OF_NERVOUS_SYSTEM_PROCESS, GOBP_REGULATION_OF_SYSTEM_PROCESS, GOBP_MONOATOMIC_ION_HOMEOSTASIS, GOCC_NEURON_PROJECTION, GOBP_REGULATION_OF_TRANSMISSION_OF_NERVE_IMPULSE, GOBP_NEURONAL_ACTION_POTENTIAL, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_SODIUM_ION_TRANSPORT, LEIN_NEURON_MARKERS

GO Biological Process (2): monoatomic cation homeostasis (GO:0055080), monoatomic cation transmembrane transport (GO:0098655)

GO Molecular Function (1): monoatomic cation channel activity (GO:0005261)

GO Cellular Component (5): plasma membrane (GO:0005886), axon (GO:0030424), cation channel complex (GO:0034703), membrane (GO:0016020), sodium channel complex (GO:0034706)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Ion channel transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monoatomic ion homeostasis	1
monoatomic cation transport	1
monoatomic ion transmembrane transport	1
monoatomic ion channel activity	1
monoatomic cation transmembrane transporter activity	1
membrane	1
cell periphery	1
neuron projection	1
monoatomic ion channel complex	1
cellular anatomical structure	1
cation channel complex	1

Protein interactions and networks

STRING

1638 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UNC80	NALCN	Q8IZF0	996
UNC80	UNC79	Q9P2D8	994
UNC80	TACR1	P25103	853
UNC80	NTS	P30990	841
UNC80	TAC1	P20366	788
UNC80	NALF1	B1AL88	781
UNC80	C2CD4A	Q8NCU7	678
UNC80	CEACAM4	O75871	542
UNC80	GK5	Q6ZS86	538
UNC80	ZNF573	Q86YE8	483
UNC80	NALF2	O75949	467
UNC80	BEST3	Q8N1M1	449
UNC80	MTSS2	Q765P7	438
UNC80	EFCAB14	O75071	436
UNC80	TMEM63B	Q5T3F8	433

IntAct

15 interactions, top by confidence:

A	B	Type	Score
CALM1	NALF1	psi-mi:“MI:0915”(physical association)	0.570
TIMMDC1	NDUFS8	psi-mi:“MI:0914”(association)	0.530
DCUN1D1	RGSL1	psi-mi:“MI:0914”(association)	0.350
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
GABARAPL2		psi-mi:“MI:0914”(association)	0.350
GABARAP		psi-mi:“MI:0914”(association)	0.350
SLC2A4	PTPRA	psi-mi:“MI:0914”(association)	0.350
HRAS	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350

BioGRID (12): UNC80 (Affinity Capture-MS), UNC80 (Affinity Capture-MS), UNC80 (Affinity Capture-MS), UNC80 (Affinity Capture-MS), UNC80 (Affinity Capture-MS), UNC80 (Affinity Capture-MS), UNC80 (Cross-Linking-MS (XL-MS)), UNC80 (Affinity Capture-MS), UNC80 (Affinity Capture-MS), UNC80 (Affinity Capture-MS), ZNF687 (Co-fractionation), ZNF827 (Co-fractionation)

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: Q8BLN6, Q8N2C7, Q9VB11

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
UNC80	“up-regulates activity”	SRC	binding
UNC80	“up-regulates activity”	NALCN	binding
UNC80	“up-regulates activity”	UNC79	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

2448 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	74
Likely pathogenic	52
Uncertain significance	1010
Likely benign	1167
Benign	62

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1028452	NM_001371986.1(UNC80):c.3042-1G>T	Pathogenic
1323741	NM_001371986.1(UNC80):c.2914C>T (p.Gln972Ter)	Pathogenic
1323742	NM_001371986.1(UNC80):c.2331+1G>T	Pathogenic
1357323	NM_001371986.1(UNC80):c.3190C>T (p.Arg1064Ter)	Pathogenic
1357913	NM_001371986.1(UNC80):c.2470C>T (p.Arg824Ter)	Pathogenic
1361501	NM_001371986.1(UNC80):c.1858C>T (p.Arg620Ter)	Pathogenic
1371926	NM_001371986.1(UNC80):c.6445C>T (p.Gln2149Ter)	Pathogenic
1373605	NM_001371986.1(UNC80):c.286C>T (p.Arg96Ter)	Pathogenic
1378288	NM_001371986.1(UNC80):c.820del (p.Thr274fs)	Pathogenic
1451796	NM_001371986.1(UNC80):c.1357C>T (p.Arg453Ter)	Pathogenic
1451819	NM_001371986.1(UNC80):c.1351G>T (p.Glu451Ter)	Pathogenic
1452883	NM_001371986.1(UNC80):c.9350_9356del (p.Asn3117fs)	Pathogenic
1454189	NM_001371986.1(UNC80):c.5476C>T (p.Gln1826Ter)	Pathogenic
1456340	NM_001371986.1(UNC80):c.7645C>T (p.Arg2549Ter)	Pathogenic
1457621	NM_001371986.1(UNC80):c.4063C>T (p.Arg1355Ter)	Pathogenic
1457938	NM_001371986.1(UNC80):c.9520C>T (p.Arg3174Ter)	Pathogenic
1458163	NM_001371986.1(UNC80):c.4846G>T (p.Glu1616Ter)	Pathogenic
1459215	NM_001371986.1(UNC80):c.8940dup (p.Tyr2981fs)	Pathogenic
1675836	NM_001371986.1(UNC80):c.4678C>T (p.Arg1560Ter)	Pathogenic
1699471	NM_001371986.1(UNC80):c.6976C>T (p.Gln2326Ter)	Pathogenic
1704946	NM_001371986.1(UNC80):c.8008C>T (p.Arg2670Ter)	Pathogenic
1927791	NM_001371986.1(UNC80):c.4566del (p.Asn1522fs)	Pathogenic
1935934	NM_001371986.1(UNC80):c.3535C>T (p.Arg1179Ter)	Pathogenic
2027133	NM_001371986.1(UNC80):c.9612_9615dup (p.Pro3206fs)	Pathogenic
2032268	NM_001371986.1(UNC80):c.5706_5710del (p.Gln1903fs)	Pathogenic
2032758	NM_001371986.1(UNC80):c.6036G>A (p.Trp2012Ter)	Pathogenic
2038989	NM_001371986.1(UNC80):c.7782dup (p.Leu2595fs)	Pathogenic
2043606	NM_001371986.1(UNC80):c.6184A>T (p.Lys2062Ter)	Pathogenic
2103634	NM_001371986.1(UNC80):c.667C>T (p.Gln223Ter)	Pathogenic
2113560	NM_001371986.1(UNC80):c.5913del (p.Glu1971fs)	Pathogenic

SpliceAI

10039 predictions. Top by Δscore:

Variant	Effect	Δscore
2:209775887:A:AG	acceptor_gain	1.0000
2:209775888:G:GA	acceptor_gain	1.0000
2:209775888:GT:G	acceptor_gain	1.0000
2:209775888:GTC:G	acceptor_gain	1.0000
2:209775888:GTCC:G	acceptor_gain	1.0000
2:209775980:TGC:T	donor_gain	1.0000
2:209776041:GCTAG:G	donor_gain	1.0000
2:209776042:C:G	donor_gain	1.0000
2:209777557:AAGG:A	donor_loss	1.0000
2:209777560:GTAA:G	donor_loss	1.0000
2:209789530:A:AG	acceptor_gain	1.0000
2:209789531:G:GG	acceptor_gain	1.0000
2:209813842:G:GG	donor_gain	1.0000
2:209816990:G:GT	donor_gain	1.0000
2:209817023:G:GT	donor_gain	1.0000
2:209817057:G:GT	donor_gain	1.0000
2:209817057:G:T	donor_gain	1.0000
2:209817102:G:GT	donor_gain	1.0000
2:209817949:G:GT	donor_gain	1.0000
2:209817950:A:T	donor_gain	1.0000
2:209818991:A:AG	acceptor_gain	1.0000
2:209818992:G:GG	acceptor_gain	1.0000
2:209818992:GT:G	acceptor_gain	1.0000
2:209818992:GTGC:G	acceptor_gain	1.0000
2:209819262:G:GG	donor_gain	1.0000
2:209820310:GGT:G	acceptor_gain	1.0000
2:209820310:GGTA:G	acceptor_gain	1.0000
2:209829225:A:AG	acceptor_gain	1.0000
2:209829229:CA:C	acceptor_loss	1.0000
2:209829230:A:AG	acceptor_gain	1.0000

AlphaMissense

21838 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:209772145:T:C	F25L	1.000
2:209772146:T:C	F25S	1.000
2:209772147:C:A	F25L	1.000
2:209772147:C:G	F25L	1.000
2:209772149:T:C	L26P	1.000
2:209772151:T:A	W27R	1.000
2:209772151:T:C	W27R	1.000
2:209773098:T:C	F33L	1.000
2:209773100:T:A	F33L	1.000
2:209773100:T:G	F33L	1.000
2:209775893:T:C	F49S	1.000
2:209775896:A:T	E50V	1.000
2:209775899:G:C	R51P	1.000
2:209775977:T:C	L77P	1.000
2:209775989:C:A	A81D	1.000
2:209776001:T:A	V85D	1.000
2:209776004:T:C	L86P	1.000
2:209776011:C:G	C88W	1.000
2:209776022:T:C	L92P	1.000
2:209776025:T:C	L93P	1.000
2:209777294:T:C	L112P	1.000
2:209777297:T:C	L113P	1.000
2:209777306:T:C	L116P	1.000
2:209786088:T:C	L208P	1.000
2:209786108:T:A	W215R	1.000
2:209786108:T:C	W215R	1.000
2:209813633:A:T	D331V	1.000
2:209813689:T:A	W350R	1.000
2:209813689:T:C	W350R	1.000
2:209813696:T:C	L352P	1.000

dbSNP variants (sampled 300 via entrez): RS1000010340 (2:209935625 G>A), RS1000076497 (2:209914546 C>G,T), RS1000093295 (2:209904644 C>A,G,T), RS1000094332 (2:209955519 A>G), RS1000114134 (2:209790390 C>T), RS1000129810 (2:209847541 A>C), RS1000141632 (2:209772839 T>G), RS1000147871 (2:209817463 G>A,T), RS1000148759 (2:209966183 G>A), RS1000150630 (2:209988103 A>G,T), RS1000161514 (2:209783715 TC>T), RS1000181888 (2:209847156 C>T), RS1000183203 (2:209806831 T>C), RS1000201014 (2:209958937 A>G), RS1000205025 (2:209931406 CACACACACACAGAT>C)

Disease associations

OMIM: gene MIM:612636 | disease phenotypes: MIM:616801, MIM:615419

GenCC curated gene-disease

Disease	Classification	Inheritance
hypotonia, infantile, with psychomotor retardation and characteristic facies 2	Definitive	Autosomal recessive
hypotonia, infantile, with psychomotor retardation and characteristic facies	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hypotonia, infantile, with psychomotor retardation and characteristic facies 2	Definitive	AR

Mondo (5): hypotonia, infantile, with psychomotor retardation and characteristic facies 2 (MONDO:0014777), intellectual disability (MONDO:0001071), hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (MONDO:0024567), hypotonia, infantile, with psychomotor retardation and characteristic facies (MONDO:0014176), microcephaly (MONDO:0001149)

Orphanet (4): Hypotonia-speech impairment-severe cognitive delay syndrome (Orphanet:371364), Hypotonia-speech impairment-severe cognitive delay syndrome due to UNC80 deficiency (Orphanet:700333), Hypotonia-speech impairment-severe cognitive delay syndrome due to NALCN deficiency (Orphanet:700336), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000194	Open mouth
HP:0000219	Thin upper lip vermilion
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000297	Facial hypotonia
HP:0000319	Smooth philtrum
HP:0000322	Short philtrum
HP:0000325	Triangular face
HP:0000337	Broad forehead
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000448	Prominent nose
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000565	Esotropia
HP:0000639	Nystagmus
HP:0000938	Osteopenia
HP:0001182	Tapered finger
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001276	Hypertonia
HP:0001290	Generalized hypotonia
HP:0001344	Absent speech

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST008058_263	Estimated glomerular filtration rate	3.000000e-08
GCST009391_1498	Metabolite levels	5.000000e-06
GCST009391_1506	Metabolite levels	2.000000e-06
GCST009856_29	Leukocyte telomere length	1.000000e-06
GCST012448_1	Anxiety x maternal smoking during pregnancy interaction	9.000000e-09
GCST012450_1	Anxiety	3.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010416	triacylglycerol 52:4 measurement
EFO:0010417	triacylglycerol 52:5 measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	8
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation, increases mutagenesis	3
Vorinostat	affects cotreatment, increases expression	2
methylmercuric chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
licochalcone B	increases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
Fulvestrant	decreases methylation, affects cotreatment	1
Caffeine	increases phosphorylation	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	increases expression	1
Lead	affects expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	decreases expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

197 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
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
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
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)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders