CLTCL1

Summary

CLTCL1 (clathrin heavy chain like 1, HGNC:2093) is a protein-coding gene on chromosome 22q11.21, encoding Clathrin heavy chain 2 (P53675). Clathrin is the major protein of the polyhedral coat of coated pits and vesicles.

This gene is a member of the clathrin heavy chain family and encodes a major protein of the polyhedral coat of coated pits and vesicles. Chromosomal aberrations involving this gene are associated with meningioma, DiGeorge syndrome, and velo-cardio-facial syndrome. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8218 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital insensitivity to pain with severe intellectual disability (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 404 total — 8 pathogenic
• Phenotypes (HPO): 29
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 2 cancer types
• MANE Select transcript: NM_007098

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2093
Approved symbol	CLTCL1
Name	clathrin heavy chain like 1
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Aliases	CLTD, CLH22, CHC22
Ensembl gene	ENSG00000070371
Ensembl biotype	protein_coding
OMIM	601273
Entrez	8218

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 34 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay

ENST00000412649, ENST00000427926, ENST00000449918, ENST00000458188, ENST00000538828, ENST00000540896, ENST00000611723, ENST00000615606, ENST00000617103, ENST00000617926, ENST00000621271, ENST00000622493, ENST00000897132, ENST00000897133, ENST00000897134, ENST00000932468, ENST00000932469, ENST00000932470, ENST00000965495, ENST00000965496, ENST00000965497, ENST00000965498, ENST00000965499, ENST00000965500, ENST00000965501, ENST00000965502, ENST00000965503, ENST00000965504, ENST00000965505, ENST00000965506, ENST00000965507, ENST00000965508, ENST00000965509, ENST00000965510, ENST00000965511, ENST00000965512, ENST00000965513, ENST00000965514, ENST00000965515, ENST00000965516, ENST00000965517

RefSeq mRNA: 2 — MANE Select: NM_007098 NM_001835, NM_007098

CCDS: CCDS46662, CCDS54497

Canonical transcript exons

ENST00000427926 — 33 exons

Exon	Start	End
ENSE00001327638	19201329	19201493
ENSE00003471523	19183390	19183611
ENSE00003472346	19208154	19208311
ENSE00003473706	19196489	19196656
ENSE00003480409	19187981	19188091
ENSE00003481354	19222684	19222809
ENSE00003484096	19225453	19225633
ENSE00003487379	19187558	19187728
ENSE00003489598	19253959	19254227
ENSE00003490030	19235696	19235869
ENSE00003497518	19221377	19221611
ENSE00003521856	19208922	19209114
ENSE00003532078	19180199	19180238
ENSE00003542749	19196266	19196415
ENSE00003542885	19191304	19191435
ENSE00003549343	19223891	19224054
ENSE00003581663	19226219	19226383
ENSE00003583442	19233166	19233318
ENSE00003584177	19233422	19233622
ENSE00003599861	19219885	19220007
ENSE00003606182	19239275	19239388
ENSE00003610933	19210326	19210509
ENSE00003612308	19180731	19180806
ENSE00003621505	19234509	19234706
ENSE00003632499	19221951	19222093
ENSE00003666384	19232476	19232598
ENSE00003672115	19229838	19229975
ENSE00003673808	19199734	19199841
ENSE00003675914	19216111	19216256
ENSE00003681145	19275623	19275830
ENSE00003684706	19242775	19242936
ENSE00003718482	19291600	19291719
ENSE00003739095	19179473	19179969

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 97.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.5404 / max 58.1696, expressed in 1329 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193142	3.5404	1329

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	97.33	gold quality
muscle of leg	UBERON:0001383	96.45	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.65	gold quality
muscle organ	UBERON:0001630	95.39	gold quality
gluteal muscle	UBERON:0002000	94.82	gold quality
triceps brachii	UBERON:0001509	94.60	gold quality
diaphragm	UBERON:0001103	94.55	silver quality
left testis	UBERON:0004533	93.16	gold quality
right testis	UBERON:0004534	92.96	gold quality
quadriceps femoris	UBERON:0001377	92.76	gold quality
skeletal muscle tissue	UBERON:0001134	92.74	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	92.68	gold quality
deltoid	UBERON:0001476	92.65	gold quality
vastus lateralis	UBERON:0001379	92.52	gold quality
tibialis anterior	UBERON:0001385	92.02	gold quality
testis	UBERON:0000473	90.98	gold quality
biceps brachii	UBERON:0001507	90.36	gold quality
muscle tissue	UBERON:0002385	89.70	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	89.39	gold quality
type B pancreatic cell	CL:0000169	88.34	gold quality
olfactory bulb	UBERON:0002264	87.93	gold quality
adrenal tissue	UBERON:0018303	87.02	gold quality
apex of heart	UBERON:0002098	87.00	gold quality
right atrium auricular region	UBERON:0006631	85.47	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.94	gold quality
cardiac atrium	UBERON:0002081	84.75	gold quality
bone marrow cell	CL:0002092	84.61	gold quality
right adrenal gland cortex	UBERON:0035827	83.59	gold quality
left adrenal gland cortex	UBERON:0035825	83.47	gold quality
right adrenal gland	UBERON:0001233	83.37	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-9801	yes	6.51
E-ANND-3	no	5.48

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

22 targeting CLTCL1, 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-4531	99.99	69.70	3181
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-1206	99.30	69.32	1016
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-3613-5P	98.40	68.91	604
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-3116	97.07	65.78	1324
HSA-MIR-4448	97.04	66.22	752
HSA-MIR-6510-3P	84.92	61.55	36
HSA-MIR-3186-3P	82.87	62.46	32

Literature-anchored findings (GeneRIF, showing 10)

• Clathrin isoform CHC22 binds to sorting nexin 5 through a coiled-coil domain. (PMID:15133132)
• role for CHC22 in formation of insulin-responsive GLUT4 compartments in muscle & adipocytes; CHC22 associated with expanded GLUT4 compartments in muscle in type 2 diabetes (PMID:19478182)
• CHC22 was required for retrograde trafficking of certain cargo molecules from endosomes to the trans-Golgi network. (PMID:20065094)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• Depletion of clathrin heavy chain (CHC)17, but not the CHC22 clathrin isoform, by ribonucleic acid interference (RNAi) induces centrosome amplification and multipolar spindles. (PMID:22891263)
• CLTCL1 is significantly upregulated in the developing human brain (PMID:26068709)
• Provide biochemical evidence for separate regulation and distinct functional niches for CHC17 and CHC22 in HeLa cells. Furthermore, the greater stability of the CHC22 coat relative to the CHC17 coat may be relevant to its excessive accumulation with GLUT4 during insulin resistance. (PMID:29097553)
• Clathrin heavy chain 22 contributes to the control of neuropeptide degradation and secretion during neuronal development. Study suggests This suggests that a reduction in CHC22 expression in sensory neural precursors may license a step in neuron precursor neurodevelopment; and that this step is mediated through control of a novel neuropeptide processing pathway. (PMID:29402896)
• These analyses suggest that ancestral human dietary change influenced selection of allotypes that affect CHC22’s role in metabolism and have potential to differentially influence the human insulin response. (PMID:31159924)
• Building GLUT4 Vesicles: CHC22 Clathrin’s Human Touch. (PMID:32620516)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cltcl1	ENSDARG00000091618
drosophila_melanogaster	Chc	FBGN0000319
caenorhabditis_elegans		WBGENE00011867

Paralogs (2): CLTC (ENSG00000141367), CLHC1 (ENSG00000162994)

Protein

Protein identifiers

Clathrin heavy chain 2 — P53675 (reviewed: P53675)

Alternative names: Clathrin heavy chain on chromosome 22

All UniProt accessions (7): P53675, A0A087WV74, A0A087WX41, A0A087WXH4, F5H5N6, H0Y529, H0YGJ9

UniProt curated annotations — full annotation on UniProt →

Function. Clathrin is the major protein of the polyhedral coat of coated pits and vesicles. Two different adapter protein complexes link the clathrin lattice either to the plasma membrane or to the trans-Golgi network.

Subunit / interactions. Clathrin triskelions, composed of 3 heavy chains and 3 light chains, are the basic subunits of the clathrin coat. In the presence of light chains, hub assembly is influenced by both the pH and the concentration of calcium. May interact with OCRL. Interacts with AFTPH/aftiphilin.

Subcellular location. Cytoplasmic vesicle membrane. Membrane. Coated pit.

Tissue specificity. Maximal levels in skeletal muscle. High levels in heart and testis. Low expression detected in all other tissues.

Domain organisation. The C-terminal third of the heavy chains forms the hub of the triskelion. This region contains the trimerization domain and the light-chain binding domain involved in the assembly of the clathrin lattice. The N-terminal seven-bladed beta-propeller is formed by WD40-like repeats, and projects inward from the polyhedral outer clathrin coat. It constitutes a major protein-protein interaction node.

Similarity. Belongs to the clathrin heavy chain family.

Isoforms (2)

UniProt ID	Names	Canonical?
P53675-1	1, Long, Brain	yes
P53675-2	2, Short, Muscle

RefSeq proteins (2): NP_001826, NP_009029* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000547	Clathrin_H-chain/VPS_repeat	Repeat
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR015348	Clathrin_H-chain_linker_core	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR016025	Clathrin_H-chain_N	Homologous_superfamily
IPR016341	Clathrin_heavy_chain	Family
IPR022365	Clathrin_H-chain_propeller_rpt	Repeat
IPR055358	CHCR	Repeat

Pfam: PF00637, PF01394, PF09268, PF13838

UniProt features (60 total): modified residue 17, region of interest 15, sequence variant 12, repeat 7, sequence conflict 6, initiator methionine 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P53675-F1	77.53	0.08

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 (17): 2, 67, 184, 394, 634, 737, 856, 899, 1167, 1206, 1229, 1441, 1441, 1477, 1487, 1494, 1501

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-190873	Gap junction degradation
R-HSA-196025	Formation of annular gap junctions
R-HSA-3928665	EPH-ephrin mediated repulsion of cells
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis

MSigDB gene sets: 221 (showing top): GOBP_CARBOHYDRATE_TRANSPORT, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, KEGG_LYSOSOME, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, MYLLYKANGAS_AMPLIFICATION_HOT_SPOT_22, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOCC_TRANS_GOLGI_NETWORK, GOCC_COATED_VESICLE, GOBP_D_GLUCOSE_IMPORT, KEGG_HUNTINGTONS_DISEASE, GOCC_GOLGI_ASSOCIATED_VESICLE, GOCC_VESICLE_COAT, GOBP_MITOTIC_CELL_CYCLE, KEGG_ENDOCYTOSIS

GO Biological Process (7): mitotic cell cycle (GO:0000278), intracellular protein transport (GO:0006886), receptor-mediated endocytosis (GO:0006898), anatomical structure morphogenesis (GO:0009653), retrograde transport, endosome to Golgi (GO:0042147), positive regulation of D-glucose import across plasma membrane (GO:0046326), vesicle-mediated transport (GO:0016192)

GO Molecular Function (3): structural molecule activity (GO:0005198), clathrin light chain binding (GO:0032051), protein binding (GO:0005515)

GO Cellular Component (17): late endosome (GO:0005770), trans-Golgi network (GO:0005802), spindle (GO:0005819), cytosol (GO:0005829), clathrin-coated pit (GO:0005905), membrane (GO:0016020), clathrin coat of trans-Golgi network vesicle (GO:0030130), coated vesicle (GO:0030135), clathrin-coated vesicle (GO:0030136), clathrin-coated endocytic vesicle (GO:0045334), extracellular exosome (GO:0070062), clathrin complex (GO:0071439), sorting endosome (GO:0097443), endomembrane system (GO:0012505), clathrin coat of coated pit (GO:0030132), cytoplasmic vesicle membrane (GO:0030659), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Gap junction trafficking	1
Gap junction degradation	1
EPH-Ephrin signaling	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
endosome	2
cytoplasm	2
cytoplasmic vesicle	2
clathrin coat	2
cell cycle	1
mitotic nuclear division	1
intracellular protein localization	1
protein transport	1
intracellular transport	1
endocytosis	1
developmental process	1
anatomical structure development	1
intercellular transport	1
endosomal transport	1
cytosolic transport	1
positive regulation of D-glucose transmembrane transport	1
regulation of D-glucose import across plasma membrane	1
D-glucose import across plasma membrane	1
transport	1
cellular process	1
molecular_function	1
clathrin binding	1
binding	1
Golgi apparatus subcompartment	1
microtubule cytoskeleton	1
intracellular membraneless organelle	1
endomembrane system	1
membrane	1
Golgi apparatus	1
trans-Golgi network transport vesicle membrane	1
clathrin vesicle coat	1
coated vesicle	1
clathrin-coated vesicle	1
endocytic vesicle	1
extracellular vesicle	1
membrane protein complex	1
vacuole	1
plasma membrane	1
clathrin-coated pit	1

Protein interactions and networks

STRING

3090 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLTCL1	CLTB	P09497	968
CLTCL1	EPN2	O95208	944
CLTCL1	CLTA	P09496	935
CLTCL1	EPN3	Q9H201	932
CLTCL1	DNAJC6	O75061	886
CLTCL1	AMPH	P49418	869
CLTCL1	CLINT1	Q14677	866
CLTCL1	SNAP91	O60641	856
CLTCL1	EPS15	P42566	849
CLTCL1	BIN1	O00499	848
CLTCL1	ATG16L1	Q676U5	841
CLTCL1	GAK	O14976	826
CLTCL1	SLC25A1	P53007	802
CLTCL1	GGA2	Q9UJY4	790
CLTCL1	AP2B1	P21851	788

IntAct

168 interactions, top by confidence:

A	B	Type	Score
HEXIM1	CCNT1	psi-mi:“MI:0914”(association)	0.930
ESR1	ESR1	psi-mi:“MI:0914”(association)	0.870
ZSCAN21	ZNF24	psi-mi:“MI:0914”(association)	0.830
PRKAG3	PRKAB2	psi-mi:“MI:0914”(association)	0.800
EGFR	GAPDH	psi-mi:“MI:0914”(association)	0.790
IFT70A	IFT56	psi-mi:“MI:0914”(association)	0.790
IFT70B	IFT56	psi-mi:“MI:0914”(association)	0.790
STAMBP	PIK3C2A	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
RXYLT1	FKTN	psi-mi:“MI:0914”(association)	0.710
STAMBPL1	PIK3C2A	psi-mi:“MI:0914”(association)	0.640
GNAI3	RGS12	psi-mi:“MI:0914”(association)	0.640
VMA12	ATP6AP2	psi-mi:“MI:0914”(association)	0.640
RAB32	CHM	psi-mi:“MI:0914”(association)	0.640
EXOSC3	MTREX	psi-mi:“MI:0914”(association)	0.640
NME3	NME4	psi-mi:“MI:0914”(association)	0.640
B2M	NEMP1	psi-mi:“MI:0914”(association)	0.640
RUVBL2	POLR3A	psi-mi:“MI:0914”(association)	0.640
METTL21C	BCKDK	psi-mi:“MI:0914”(association)	0.640
HIP1	CLTCL1	psi-mi:“MI:0407”(direct interaction)	0.610
HIP1	CLTCL1	psi-mi:“MI:0915”(physical association)	0.610
CLTCL1	HIP1	psi-mi:“MI:0403”(colocalization)	0.610
rep	CLTCL1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (245): CLTCL1 (Affinity Capture-RNA), CLTCL1 (Affinity Capture-RNA), CLTCL1 (Affinity Capture-RNA), CLTCL1 (Affinity Capture-MS), CLTCL1 (Affinity Capture-MS), CLTCL1 (Affinity Capture-MS), CLTCL1 (Affinity Capture-MS), CLTCL1 (Affinity Capture-MS), CLTCL1 (Affinity Capture-MS), CLTCL1 (Affinity Capture-MS), CLTCL1 (Affinity Capture-MS), AHSA1 (Co-fractionation), ATP1A1 (Co-fractionation), CCT6B (Co-fractionation), CLTCL1 (Co-fractionation)

ESM2 similar proteins: A0A644F649, A0AVF1, A1Z8E9, A4III8, A8BS40, A8JA42, A8XBR9, B5X0I6, O17581, O42668, O74458, O76094, O94459, O94474, P11442, P19735, P25870, P29742, P33731, P34574, P41889, P49951, P49965, P53675, P89105, Q00610, Q03560, Q13099, Q16JL4, Q20255, Q29L58, Q4R7Z9, Q57ZL2, Q5CZ52, Q5PR66, Q5U2N8, Q61LA1, Q68FD5, Q6GKV1, Q6INC1

Diamond homologs: P11442, P22137, P25870, P29742, P34574, P49951, P53675, Q00610, Q0WLB5, Q0WNJ6, Q10161, Q2QYW2, Q2RBN7, Q5XIR8, Q68FD5

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
PICALM	up-regulates	CLTCL1	binding
ATG16L1	up-regulates	CLTCL1	binding
CLTCL1	“form complex”	“AP-2/clathrin vescicle”	binding
CLTCL1	“form complex”	“AP-3/clathrin vescicle”	binding
CLTCL1	“form complex”	“AP-1/clathrin vescicle”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 242 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
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	5	12.2×	9e-03
Golgi Associated Vesicle Biogenesis	8	9.9×	4e-04
Cargo recognition for clathrin-mediated endocytosis	13	8.4×	2e-06
Clathrin-mediated endocytosis	15	7.9×	6e-07

GO biological processes:

GO term	Partners	Fold	FDR
clathrin coat assembly	8	33.2×	6e-08
clathrin-dependent endocytosis	7	19.0×	4e-05
RNA processing	8	8.2×	2e-03
endocytosis	13	5.8×	2e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 2 cancer types — HCC, PRAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	0
Uncertain significance	278
Likely benign	45
Benign	30

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1077187	Single allele	Pathogenic
147730	GRCh38/hg38 22q11.21(chr22:18087546-19196905)x3	Pathogenic
150093	GRCh38/hg38 22q11.21(chr22:18339130-21151156)x3	Pathogenic
1703644	GRCh37/hg19 22q11.21(chr22:18893344-21650280)	Pathogenic
253416	GRCh37/hg19 22q11.21(chr22:18900442-21440514)x1	Pathogenic
625586	GRCh37/hg19 22q11.21(chr22:18901004-21408430)	Pathogenic
625621	GRCh37/hg19 22q11.21(chr22:18912403-21431174)	Pathogenic
816509	GRCh37/hg19 22q11.21(chr22:18892575-20306993)x3	Pathogenic

SpliceAI

6181 predictions. Top by Δscore:

Variant	Effect	Δscore
22:19180728:TA:T	donor_loss	1.0000
22:19180729:A:AC	donor_gain	1.0000
22:19180730:C:CC	donor_gain	1.0000
22:19180730:CCAAA:C	donor_gain	1.0000
22:19180802:TCCAC:T	acceptor_gain	1.0000
22:19180803:CCAC:C	acceptor_gain	1.0000
22:19180803:CCACC:C	acceptor_gain	1.0000
22:19180804:CAC:C	acceptor_gain	1.0000
22:19180804:CACC:C	acceptor_gain	1.0000
22:19180805:AC:A	acceptor_gain	1.0000
22:19180805:ACC:A	acceptor_loss	1.0000
22:19180806:CC:C	acceptor_gain	1.0000
22:19180806:CCT:C	acceptor_loss	1.0000
22:19180807:C:CC	acceptor_gain	1.0000
22:19180807:CTG:C	acceptor_loss	1.0000
22:19180810:C:CT	acceptor_gain	1.0000
22:19183386:CTACC:C	donor_loss	1.0000
22:19183387:TACCT:T	donor_loss	1.0000
22:19183389:C:CA	donor_loss	1.0000
22:19187554:CAA:C	donor_loss	1.0000
22:19187555:AACCT:A	donor_loss	1.0000
22:19187557:C:CG	donor_loss	1.0000
22:19187977:CCAC:C	donor_loss	1.0000
22:19187978:CACC:C	donor_loss	1.0000
22:19187979:ACCTG:A	donor_loss	1.0000
22:19187980:CCTGA:C	donor_loss	1.0000
22:19191299:CTCA:C	donor_loss	1.0000
22:19191300:TCACC:T	donor_loss	1.0000
22:19191301:CACC:C	donor_loss	1.0000
22:19191302:A:AC	donor_gain	1.0000

AlphaMissense

10887 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:19254141:A:G	W113R	0.996
22:19254141:A:T	W113R	0.996
22:19253988:A:G	W164R	0.991
22:19253988:A:T	W164R	0.991
22:19254090:A:G	W130R	0.991
22:19254090:A:T	W130R	0.991
22:19275760:A:T	I38K	0.991
22:19275631:G:T	A81D	0.990
22:19254147:A:G	W111R	0.987
22:19254147:A:T	W111R	0.987
22:19275792:G:C	F27L	0.986
22:19275792:G:T	F27L	0.986
22:19275794:A:G	F27L	0.986
22:19208994:C:G	A1124P	0.984
22:19253984:A:G	L165P	0.984
22:19254012:A:C	Y156D	0.983
22:19275651:A:C	N74K	0.983
22:19275651:A:T	N74K	0.983
22:19254139:C:A	W113C	0.981
22:19254139:C:G	W113C	0.981
22:19275628:A:G	L82P	0.980
22:19275762:G:C	F37L	0.979
22:19275762:G:T	F37L	0.979
22:19275764:A:G	F37L	0.979
22:19239290:A:C	F260L	0.978
22:19239290:A:T	F260L	0.978
22:19239292:A:G	F260L	0.978
22:19275760:A:C	I38R	0.978
22:19254098:A:T	V127D	0.976
22:19254119:G:T	A120D	0.976

dbSNP variants (sampled 300 via entrez): RS1000037076 (22:19256529 G>A), RS1000062880 (22:19291388 G>A), RS1000174627 (22:19280952 G>C), RS1000215580 (22:19200612 G>A), RS1000236304 (22:19245381 A>G,T), RS1000264728 (22:19261858 T>C), RS1000304819 (22:19197980 A>G), RS1000398149 (22:19192440 A>C), RS1000411591 (22:19197288 A>C,G), RS1000415605 (22:19197553 T>C), RS1000457159 (22:19278335 G>A), RS1000482245 (22:19205363 A>G), RS1000488864 (22:19292731 A>C), RS1000504433 (22:19286285 G>A), RS1000505682 (22:19251021 G>T)

Disease associations

OMIM: gene MIM:601273 | disease phenotypes: MIM:188400, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital insensitivity to pain with severe intellectual disability	Supportive	Autosomal recessive
multiple congenital anomalies/dysmorphic syndrome	Limited	Autosomal dominant

Mondo (4): DiGeorge syndrome (MONDO:0008564), autism (MONDO:0005260), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042), congenital insensitivity to pain with severe intellectual disability (MONDO:0018682)

Orphanet (1): 22q11.2 deletion syndrome (Orphanet:567)

HPO phenotypes

29 total (30 of 29 shown, HPO-id order):

HPO	Term
HP:0000324	Facial asymmetry
HP:0000347	Micrognathia
HP:0000448	Prominent nose
HP:0000486	Strabismus
HP:0000491	Keratitis
HP:0000742	Self-mutilation
HP:0001328	Specific learning disability
HP:0001518	Small for gestational age
HP:0001562	Oligohydramnios
HP:0001772	Talipes equinovalgus
HP:0001838	Rocker bottom foot
HP:0001999	Abnormal facial shape
HP:0002069	Bilateral tonic-clonic seizure
HP:0002188	Delayed CNS myelination
HP:0002754	Osteomyelitis
HP:0002757	Recurrent fractures
HP:0002982	Tibial bowing
HP:0007021	Pain insensitivity
HP:0008000	Decreased corneal reflex
HP:0008780	Congenital bilateral hip dislocation
HP:0008947	Floppy infant
HP:0009826	Limb undergrowth
HP:0010830	Impaired tactile sensation
HP:0010841	Multifocal epileptiform discharges
HP:0011344	Severe global developmental delay
HP:0011470	Nasogastric tube feeding in infancy
HP:0012044	Seesaw nystagmus
HP:0012745	Short palpebral fissure
HP:0200020	Corneal erosion
HP:0000717	Autism

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001639_30	Metabolite levels	3.000000e-11
GCST003075_3	Cognitive decline rate in late mild cognitive impairment	4.000000e-06
GCST003075_67	Cognitive decline rate in late mild cognitive impairment	9.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0007710	cognitive decline measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D004062	DiGeorge Syndrome	C05.660.207.103.500; C14.240.400.021.500; C14.280.400.044.500; C15.604.451.249.500; C16.131.077.019.500; C16.131.240.400.021.500; C16.131.260.019.500; C16.131.482.249.500; C16.131.621.207.103.500; C16.320.180.019.500; C19.642.482.500.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	increases expression	2
Air Pollutants	affects cotreatment, decreases expression, increases abundance, affects expression	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
bisphenol A	affects cotreatment, decreases methylation	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
sodium arsenite	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
cupric oxide	increases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
bisphenol S	decreases methylation	1
Sunitinib	increases expression	1
Fulvestrant	decreases methylation, affects cotreatment	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Amiodarone	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Calcitriol	decreases expression	1
Carmustine	increases expression	1
Ozone	affects cotreatment, decreases expression, increases abundance	1
Tretinoin	increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases methylation	1
Particulate Matter	affects expression, increases abundance	1
Volatile Organic Compounds	affects cotreatment, decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1NN	Abcam HeLa CLTCL1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With 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
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
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
NCT00395538	PHASE3	TERMINATED	Effects of PTH Replacement on Bone in Hypoparathyroidism
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism