TMEM63A

Summary

TMEM63A (transmembrane protein 63A, HGNC:29118) is a protein-coding gene on chromosome 1q42.12, encoding Mechanosensitive cation channel TMEM63A (O94886). Mechanosensitive cation channel with low conductance and high activation threshold.

Enables mechanosensitive monoatomic ion channel activity. Predicted to be involved in surfactant secretion. Located in bounding membrane of organelle; centriolar satellite; and plasma membrane. Implicated in hypomyelinating leukodystrophy 19.

Source: NCBI Gene 9725 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukodystrophy, hypomyelinating, 19, transient infantile (Strong, GenCC)
• Clinical variants (ClinVar): 226 total — 3 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 16
• Druggable target: yes
• MANE Select transcript: NM_014698

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29118
Approved symbol	TMEM63A
Name	transmembrane protein 63A
Location	1q42.12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000196187
Ensembl biotype	protein_coding
OMIM	618685
Entrez	9725

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 13 protein_coding, 5 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000366835, ENST00000436966, ENST00000474478, ENST00000482753, ENST00000483779, ENST00000487817, ENST00000487971, ENST00000496025, ENST00000537914, ENST00000900920, ENST00000900921, ENST00000900922, ENST00000900923, ENST00000900924, ENST00000900925, ENST00000923513, ENST00000954243, ENST00000954244, ENST00000954245

RefSeq mRNA: 1 — MANE Select: NM_014698 NM_014698

CCDS: CCDS31042

Canonical transcript exons

ENST00000366835 — 25 exons

Exon	Start	End
ENSE00000961962	225871987	225872053
ENSE00000961963	225871076	225871113
ENSE00000961964	225867888	225868030
ENSE00000961965	225867112	225867163
ENSE00000961966	225866574	225866682
ENSE00000961972	225859196	225859349
ENSE00000961974	225856652	225856738
ENSE00000961975	225855878	225855940
ENSE00000961976	225853629	225853791
ENSE00000961977	225852664	225852769
ENSE00000961978	225849912	225850079
ENSE00001015499	225848897	225849012
ENSE00001071044	225847034	225847213
ENSE00001286263	225865897	225865967
ENSE00001286300	225860860	225860997
ENSE00001435173	225879220	225879410
ENSE00001442720	225845536	225846932
ENSE00001442724	225877395	225877594
ENSE00001442725	225882304	225882380
ENSE00003471182	225862771	225862851
ENSE00003489139	225856911	225857017
ENSE00003545178	225862218	225862351
ENSE00003572269	225862455	225862578
ENSE00003594321	225848492	225848554
ENSE00003682827	225874288	225874367

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 98.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.2023 / max 537.7751, expressed in 1805 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17729	20.2064	1801
17730	1.4458	890
17722	1.0582	78
17725	0.8050	78
17721	0.4467	71
17723	0.1482	58
17724	0.0698	40
17719	0.0221	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	98.82	gold quality
right uterine tube	UBERON:0001302	98.46	gold quality
middle frontal gyrus	UBERON:0002702	97.96	gold quality
body of pancreas	UBERON:0001150	97.65	gold quality
spinal cord	UBERON:0002240	97.65	gold quality
minor salivary gland	UBERON:0001830	97.62	gold quality
corpus callosum	UBERON:0002336	97.45	gold quality
buccal mucosa cell	CL:0002336	96.95	gold quality
saliva-secreting gland	UBERON:0001044	96.82	gold quality
granulocyte	CL:0000094	96.58	gold quality
rectum	UBERON:0001052	96.35	gold quality
endocervix	UBERON:0000458	96.06	gold quality
transverse colon	UBERON:0001157	95.87	gold quality
mucosa of stomach	UBERON:0001199	95.73	gold quality
body of stomach	UBERON:0001161	95.69	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.57	gold quality
metanephros cortex	UBERON:0010533	95.51	gold quality
gall bladder	UBERON:0002110	95.45	gold quality
right ovary	UBERON:0002118	95.42	gold quality
apex of heart	UBERON:0002098	95.23	gold quality
sural nerve	UBERON:0015488	95.20	gold quality
stomach	UBERON:0000945	95.07	gold quality
left ovary	UBERON:0002119	95.07	gold quality
colonic epithelium	UBERON:0000397	94.99	gold quality
body of uterus	UBERON:0009853	94.88	gold quality
mouth mucosa	UBERON:0003729	94.81	gold quality
inferior vagus X ganglion	UBERON:0005363	94.78	gold quality
mucosa of transverse colon	UBERON:0004991	94.70	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.52	gold quality
upper lobe of left lung	UBERON:0008952	94.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	25.77
E-ANND-3	yes	5.64

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

34 targeting TMEM63A, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-5190	99.15	67.76	1234
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-4711-3P	98.97	66.87	1020
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-3190-5P	98.87	64.89	1345
HSA-MIR-2355-5P	98.83	65.51	1589
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-3945	98.68	64.21	553
HSA-MIR-193A-3P	98.59	66.36	769
HSA-MIR-193B-3P	98.59	66.62	748

Literature-anchored findings (GeneRIF, showing 3)

• Spinal cord involvement and paroxysmal events in ““Infantile Onset Transient Hypomyelination”” due to TMEM63A mutation. (PMID:33785861)
• Stretch response of the mechano-gated channel TMEM63A in membrane patches and single cells. (PMID:38189136)
• A monomeric structure of human TMEM63A protein. (PMID:38217391)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem63a	ENSDARG00000031956
mus_musculus	Tmem63a	ENSMUSG00000026519
rattus_norvegicus	Tmem63a	ENSRNOG00000003310

Paralogs (2): TMEM63B (ENSG00000137216), TMEM63C (ENSG00000165548)

Protein

Protein identifiers

Mechanosensitive cation channel TMEM63A — O94886 (reviewed: O94886)

Alternative names: Transmembrane protein 63A

All UniProt accessions (3): O94886, Q2HIZ8, X6RI56

UniProt curated annotations — full annotation on UniProt →

Function. Mechanosensitive cation channel with low conductance and high activation threshold. In contrast to TMEM63B, does not show phospholipid scramblase activity. Acts as a regulator of lysosomal morphology by mediating lysosomal mechanosensitivity. Important for the baby’s first breath and respiration throughout life. Upon lung inflation conducts cation currents in alveolar type 1 and 2 cells triggering lamellar body exocytosis and surfactant secretion into airspace. Also acts as an osmosensitive cation channel preferentially activated by hypotonic stress.

Subunit / interactions. Monomer.

Subcellular location. Lysosome membrane. Early endosome membrane. Cell membrane.

Post-translational modifications. N-Glycosylated.

Disease relevance. Leukodystrophy, hypomyelinating, 19, transient infantile (HLD19) [MIM:618688] An autosomal dominant disorder characterized by marked hypomyelination on brain imaging, congenital nystagmus, and motor delay manifesting in early infancy. Both neurologic impairment and abnormal brain imaging spontaneously resolve during childhood. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the CSC1 (TC 1.A.17) family.

RefSeq proteins (1): NP_055513* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003864	CSC1/OSCA1-like_7TM	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR027815	CSC1/OSCA1-like_cyt	Domain
IPR032880	CSC1/OSCA1-like_N	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR045122	Csc1-like	Family

Pfam: PF02714, PF13967, PF14703

Catalyzed reactions (Rhea), 1 shown:

• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)

UniProt features (76 total): helix 22, topological domain 12, transmembrane region 11, strand 10, sequence variant 9, sequence conflict 3, region of interest 2, glycosylation site 2, turn 2, chain 1, modified residue 1, mutagenesis site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
9N93	ELECTRON MICROSCOPY	2.95
8GRS	ELECTRON MICROSCOPY	3.3
8WUA	ELECTRON MICROSCOPY	3.6
9N95	ELECTRON MICROSCOPY	3.65
8EHW	ELECTRON MICROSCOPY	3.8
9WXV	ELECTRON MICROSCOPY	4.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94886-F1	74.70	0.29

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 (1): 739

Glycosylation sites (2): 38, 450

Mutagenesis-validated functional residues (1):

Position	Phenotype
571	significant loss of mechanosensitive ion channel activity but no effect on its localization to the cell membrane.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 252 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_VACUOLE_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, PEREZ_TP63_TARGETS, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_MONOATOMIC_CATION_TRANSPORT, WATANABE_RECTAL_CANCER_RADIOTHERAPY_RESPONSIVE_UP, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, GOCC_CENTROSOME, GOBP_SECRETION, BOYAULT_LIVER_CANCER_SUBCLASS_G1_UP, DOUGLAS_BMI1_TARGETS_DN, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS

GO Biological Process (5): lysosome organization (GO:0007040), surfactant secretion (GO:0160069), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), monoatomic cation transmembrane transport (GO:0098655)

GO Molecular Function (5): nucleic acid binding (GO:0003676), calcium-activated cation channel activity (GO:0005227), mechanosensitive monoatomic ion channel activity (GO:0008381), osmolarity-sensing monoatomic cation channel activity (GO:1990760), protein binding (GO:0005515)

GO Cellular Component (10): lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), early endosome membrane (GO:0031901), centriolar satellite (GO:0034451), specific granule membrane (GO:0035579), extracellular exosome (GO:0070062), tertiary granule membrane (GO:0070821), lysosome (GO:0005764), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
gated channel activity	2
cellular anatomical structure	2
secretory granule membrane	2
lytic vacuole organization	1
surfactant homeostasis	1
secretion	1
transport	1
monoatomic ion transport	1
transmembrane transport	1
monoatomic cation transport	1
monoatomic ion transmembrane transport	1
monoatomic ion-gated channel activity	1
ligand-gated monoatomic cation channel activity	1
monoatomic ion channel activity	1
osmosensor activity	1
monoatomic cation channel activity	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
early endosome	1
endosome membrane	1
centrosome	1
specific granule	1
extracellular vesicle	1
tertiary granule	1
lytic vacuole	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

652 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM63A	TMEM147	Q9BVK8	651
TMEM63A	GALM	Q96C23	576
TMEM63A	ZNF157	P51786	509
TMEM63A	TMEM120A	Q9BXJ8	461
TMEM63A	FXYD3	Q14802	435
TMEM63A	TMEM234	Q8WY98	426
TMEM63A	SLC67A1-AS	Q8N1D0	418
TMEM63A	SNX30	Q5VWJ9	413
TMEM63A	PYCR2	Q96C36	411
TMEM63A	PRSS8	Q16651	410
TMEM63A	GNB3	P16520	404
TMEM63A	SCNN1A	P37088	404
TMEM63A	NCLN	Q969V3	398
TMEM63A	IRF6	O14896	389
TMEM63A	MRPS35	P82673	382

IntAct

52 interactions, top by confidence:

A	B	Type	Score
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
C3AR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
TMEM63A	AP3B1	psi-mi:“MI:0914”(association)	0.530
SLC44A5	NME2P1	psi-mi:“MI:0914”(association)	0.530
SLC51A	TMEM63A	psi-mi:“MI:0914”(association)	0.530
TCIRG1	AP3D1	psi-mi:“MI:0914”(association)	0.530
SLC30A2	RER1	psi-mi:“MI:0914”(association)	0.530
PTGIR	TMEM63A	psi-mi:“MI:0914”(association)	0.530
TMEM63A	AP3D1	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
TMEM63A	CCR2	psi-mi:“MI:0915”(physical association)	0.370
TMEM63A	DRD2	psi-mi:“MI:0915”(physical association)	0.370
TMEM63A	GPR37	psi-mi:“MI:0915”(physical association)	0.370
TMEM63A	CREB3	psi-mi:“MI:0915”(physical association)	0.370
LGALS8	SLC22A23	psi-mi:“MI:0914”(association)	0.350
SLC4A8	ABCC4	psi-mi:“MI:0914”(association)	0.350
ATP2B2	GPR89A	psi-mi:“MI:0914”(association)	0.350
SLC45A2	TMEM63A	psi-mi:“MI:0914”(association)	0.350
TPRA1	BMPR1B	psi-mi:“MI:0914”(association)	0.350
PTGIR	GPAA1	psi-mi:“MI:0914”(association)	0.350
HTR3A	GPAA1	psi-mi:“MI:0914”(association)	0.350
NMUR2	TMEM63A	psi-mi:“MI:0914”(association)	0.350
ATP2B2	ESYT2	psi-mi:“MI:0914”(association)	0.350
TTMP	TMEM223	psi-mi:“MI:0914”(association)	0.350

BioGRID (139): TMEM63A (Affinity Capture-MS), TMEM63A (Affinity Capture-MS), TMEM63A (Affinity Capture-MS), AP3S2 (Affinity Capture-MS), MFSD10 (Affinity Capture-MS), AP3S1 (Affinity Capture-MS), AP3B1 (Affinity Capture-MS), PTPN1 (Affinity Capture-MS), LGALS3 (Affinity Capture-MS), TMEM63A (Affinity Capture-MS), TMEM63A (Affinity Capture-MS), YIPF4 (Affinity Capture-MS), TMEM63A (Affinity Capture-MS), PIGN (Affinity Capture-MS), MFSD5 (Affinity Capture-MS)

ESM2 similar proteins: A0A452G813, A0A8V0ZB02, A1L3G9, A2AWR3, A9LIW2, B6HTR9, D3ZNF5, F4I248, F4JCY2, O35379, O57428, O94886, O94911, P08983, Q059Y8, Q06538, Q09427, Q09428, Q09429, Q17JQ7, Q3KTM2, Q3TWI9, Q4R7U0, Q4V8U5, Q5GH22, Q5GH60, Q5GH68, Q5R826, Q5R9A7, Q5T3F8, Q5YCC5, Q6NP91, Q6PP77, Q6UR05, Q7Q5R7, Q7Z3F1, Q7Z402, Q8C428, Q8CBX0, Q8CG09

Diamond homologs: A0A452G813, A0A8V0ZB02, D3ZNF5, O94886, Q3TWI9, Q5R826, Q5T3F8, Q6NP91, Q8CBX0, Q91YT8, Q9P1W3, X1WEM4, Q9SZT4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 59 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
Class A/1 (Rhodopsin-like receptors)	6	12.4×	3e-04
Peptide ligand-binding receptors	6	12.4×	3e-04
GPCR ligand binding	6	10.7×	5e-04
G alpha (i) signalling events	8	8.7×	3e-04
GPCR downstream signalling	6	7.2×	4e-03
Signaling by GPCR	6	6.7×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
chemotaxis	6	15.4×	1e-03
positive regulation of cytosolic calcium ion concentration	6	13.2×	2e-03
inflammatory response	8	5.7×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	5
Uncertain significance	117
Likely benign	43
Benign	9

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1698712	NM_014698.3(TMEM63A):c.1675T>C (p.Tyr559His)	Pathogenic
689459	NM_014698.3(TMEM63A):c.503G>A (p.Gly168Glu)	Pathogenic
689460	NM_014698.3(TMEM63A):c.1385T>A (p.Ile462Asn)	Pathogenic
3068720	NM_014698.3(TMEM63A):c.1658G>A (p.Gly553Asp)	Likely pathogenic
3900600	NM_014698.3(TMEM63A):c.1699G>T (p.Gly567Cys)	Likely pathogenic
3900601	NM_014698.3(TMEM63A):c.583del (p.Leu195fs)	Likely pathogenic
3900602	NM_014698.3(TMEM63A):c.2066G>A (p.Arg689His)	Likely pathogenic
3900603	NM_014698.3(TMEM63A):c.1657G>A (p.Gly553Ser)	Likely pathogenic

SpliceAI

4307 predictions. Top by Δscore:

Variant	Effect	Δscore
1:225848490:A:AC	donor_gain	1.0000
1:225848491:C:CC	donor_gain	1.0000
1:225849910:AC:A	donor_gain	1.0000
1:225849911:CC:C	donor_gain	1.0000
1:225850077:GGCC:G	acceptor_loss	1.0000
1:225850080:C:CA	acceptor_loss	1.0000
1:225850080:C:CC	acceptor_gain	1.0000
1:225852656:CCACT:C	donor_loss	1.0000
1:225852657:CACTC:C	donor_loss	1.0000
1:225852658:ACTCA:A	donor_loss	1.0000
1:225852659:CTCAC:C	donor_loss	1.0000
1:225852660:T:TA	donor_loss	1.0000
1:225852661:C:CC	donor_loss	1.0000
1:225852662:A:AC	donor_gain	1.0000
1:225852662:ACC:A	donor_loss	1.0000
1:225852663:C:CA	donor_loss	1.0000
1:225852663:C:CC	donor_gain	1.0000
1:225853623:TGGCA:T	donor_loss	1.0000
1:225853624:GGCAC:G	donor_loss	1.0000
1:225853625:GCACC:G	donor_loss	1.0000
1:225853626:CACC:C	donor_loss	1.0000
1:225853628:C:CG	donor_loss	1.0000
1:225853628:CCTG:C	donor_gain	1.0000
1:225853640:T:A	donor_gain	1.0000
1:225853787:CGCAC:C	acceptor_gain	1.0000
1:225853789:CAC:C	acceptor_gain	1.0000
1:225853792:CT:C	acceptor_loss	1.0000
1:225855876:A:AC	donor_gain	1.0000
1:225855877:C:CC	donor_gain	1.0000
1:225855936:CTAGA:C	acceptor_gain	1.0000

AlphaMissense

5311 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:225852692:G:C	S625R	0.998
1:225852692:G:T	S625R	0.998
1:225852694:T:G	S625R	0.998
1:225852664:C:G	G635R	0.997
1:225850079:C:T	G635D	0.996
1:225853758:A:C	F556L	0.996
1:225853758:A:T	F556L	0.996
1:225853760:A:G	F556L	0.996
1:225867144:A:C	F178L	0.996
1:225867144:A:T	F178L	0.996
1:225867145:A:C	F178C	0.996
1:225867146:A:G	F178L	0.996
1:225853769:C:G	G553R	0.995
1:225852681:G:C	P629R	0.994
1:225852681:G:T	P629H	0.994
1:225852683:A:C	C628W	0.994
1:225852685:A:G	C628R	0.994
1:225853783:A:C	F548C	0.994
1:225853790:A:G	C546R	0.994
1:225856670:G:T	P518H	0.994
1:225856980:A:T	L472H	0.994
1:225867907:G:C	N165K	0.994
1:225867907:G:T	N165K	0.994
1:225853759:A:C	F556C	0.993
1:225853782:G:C	F548L	0.993
1:225853782:G:T	F548L	0.993
1:225853784:A:G	F548L	0.993
1:225856670:G:C	P518R	0.993
1:225856980:A:G	L472P	0.993
1:225853747:A:T	V560D	0.992

dbSNP variants (sampled 300 via entrez): RS1000023800 (1:225869542 GCCT>G), RS1000055447 (1:225843180 C>CA), RS1000110791 (1:225854329 CA>C), RS1000191841 (1:225856194 T>G), RS1000210921 (1:225865290 C>A,T), RS1000456553 (1:225841370 C>T), RS1000532687 (1:225857483 G>A,T), RS1000585139 (1:225857692 A>C), RS1000702271 (1:225870140 G>A,C), RS1000766704 (1:225880737 C>T), RS1000812829 (1:225863832 C>T), RS1000844667 (1:225846087 C>T), RS1000846024 (1:225850712 ATGTC>A), RS1000873767 (1:225862658 C>A,T), RS1000896971 (1:225846315 G>A,T)

Disease associations

OMIM: gene MIM:618685 | disease phenotypes: MIM:618688, MIM:312080

GenCC curated gene-disease

Disease	Classification	Inheritance
leukodystrophy, hypomyelinating, 19, transient infantile	Strong	Autosomal dominant

Mondo (2): leukodystrophy, hypomyelinating, 19, transient infantile (MONDO:0032871), leukodystrophy (MONDO:0019046)

Orphanet (1): Leukodystrophy (Orphanet:68356)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000047	Hypospadias
HP:0000545	Myopia
HP:0000648	Optic atrophy
HP:0001251	Ataxia
HP:0001290	Generalized hypotonia
HP:0001310	Dysmetria
HP:0001328	Specific learning disability
HP:0002080	Intention tremor
HP:0002188	Delayed CNS myelination
HP:0002415	Leukodystrophy
HP:0002421	Poor head control
HP:0002599	Head titubation
HP:0003487	Babinski sign
HP:0012043	Pendular nystagmus
HP:0031936	Delayed ability to walk

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066437 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1051741	EPHX1, TMEM63A		0.00	0

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.97	Kd	1082	nM	CHEMBL5653589
5.97	ED50	1082	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149616: Binding affinity to human TMEM63A incubated for 45 mins by Kinobead based pull down assay	kd	1.0815	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
mercuric bromide	increases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol A	increases methylation, affects cotreatment	1
manganese chloride	decreases expression, increases abundance, 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
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Cisplatin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Methyl Methanesulfonate	increases expression	1
Selenium	increases expression	1
Smoke	decreases expression	1
Dronabinol	increases expression	1
Theophylline	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
Vitamin E	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Aflatoxin B1	decreases expression	1
Cadmium Chloride	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652658	Binding	Binding affinity to human TMEM63A incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_YA82	IDG-HEK293T-TMEM63A-V5-OE	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00889174	Not specified	COMPLETED	The Nosology and Etiology of Leukodystrophies of Unknown Causes
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02843555	Not specified	COMPLETED	Natural History of the Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT03639285	Not specified	RECRUITING	Natural History, Diagnosis, and Outcomes for Leukodystrophies
NCT05443906	Not specified	RECRUITING	Home Exercise for Individuals with Neurodegenerative Disease