TMEM63B

Summary

TMEM63B (transmembrane protein 63B, HGNC:17735) is a protein-coding gene on chromosome 6p21.1, encoding Mechanosensitive cation channel TMEM63B (Q5T3F8). Mechanosensitive cation channel with low conductance and high activation threshold.

Enables mechanosensitive monoatomic cation channel activity. Predicted to be involved in sensory perception of sound and surfactant secretion. Located in actin cytoskeleton; cytoplasmic vesicle membrane; and plasma membrane.

Source: NCBI Gene 55362 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 140 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 67
• MANE Select transcript: NM_018426

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17735
Approved symbol	TMEM63B
Name	transmembrane protein 63B
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp434P0531, dJ421H19.2
Ensembl gene	ENSG00000137216
Ensembl biotype	protein_coding
OMIM	619952
Entrez	55362

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 27 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000259746, ENST00000323267, ENST00000371893, ENST00000497371, ENST00000525294, ENST00000525873, ENST00000527188, ENST00000532634, ENST00000533121, ENST00000534326, ENST00000872088, ENST00000872089, ENST00000872090, ENST00000872091, ENST00000872092, ENST00000872093, ENST00000872094, ENST00000872095, ENST00000872096, ENST00000872097, ENST00000872098, ENST00000872099, ENST00000872100, ENST00000872101, ENST00000872102, ENST00000930277, ENST00000930278, ENST00000930279, ENST00000930280, ENST00000930281, ENST00000967672, ENST00000967673, ENST00000967674

RefSeq mRNA: 2 — MANE Select: NM_018426 NM_001318792, NM_018426

CCDS: CCDS34461

Canonical transcript exons

ENST00000323267 — 24 exons

Exon	Start	End
ENSE00002174179	44127554	44127678
ENSE00003461734	44138480	44138517
ENSE00003463265	44135328	44135366
ENSE00003489279	44146847	44146927
ENSE00003505124	44136349	44136439
ENSE00003506326	44134561	44134743
ENSE00003511653	44135017	44135096
ENSE00003528618	44140252	44140360
ENSE00003568202	44147377	44147500
ENSE00003571880	44139467	44139609
ENSE00003576250	44139708	44139759
ENSE00003615199	44148513	44148650
ENSE00003621930	44148252	44148385
ENSE00003666862	44154692	44155519
ENSE00003689661	44141028	44141098
ENSE00003889548	44154073	44154188
ENSE00003890787	44152593	44152698
ENSE00003891181	44153676	44153843
ENSE00003892347	44150224	44150310
ENSE00003893675	44149859	44149965
ENSE00003894065	44150564	44150629
ENSE00003894110	44148792	44148945
ENSE00003894959	44154365	44154445
ENSE00003895885	44151846	44152008

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 96.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.3810 / max 271.6261, expressed in 1815 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67967	14.1455	1788
67968	8.1413	1653
67964	4.0613	1100
67969	0.4009	213
67974	0.3723	197
67970	0.2123	133
67973	0.0301	16
67972	0.0171	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cardiac muscle of right atrium	UBERON:0003379	96.72	gold quality
cortical plate	UBERON:0005343	96.24	gold quality
left ventricle myocardium	UBERON:0006566	96.19	gold quality
nasal cavity epithelium	UBERON:0005384	95.71	gold quality
kidney epithelium	UBERON:0004819	95.52	gold quality
upper arm skin	UBERON:0004263	95.31	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.81	gold quality
lower esophagus mucosa	UBERON:0035834	93.71	gold quality
cerebellar vermis	UBERON:0004720	93.68	gold quality
gastrocnemius	UBERON:0001388	93.61	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.52	gold quality
upper lobe of left lung	UBERON:0008952	93.37	gold quality
vena cava	UBERON:0004087	93.34	gold quality
dorsal root ganglion	UBERON:0000044	93.25	gold quality
body of tongue	UBERON:0011876	93.22	gold quality
cardia of stomach	UBERON:0001162	93.14	gold quality
cerebellar hemisphere	UBERON:0002245	93.11	gold quality
skin of leg	UBERON:0001511	93.10	gold quality
cerebellar cortex	UBERON:0002129	93.07	gold quality
right testis	UBERON:0004534	93.07	gold quality
lateral globus pallidus	UBERON:0002476	93.06	gold quality
upper lobe of lung	UBERON:0008948	92.99	gold quality
right lung	UBERON:0002167	92.96	gold quality
mucosa of transverse colon	UBERON:0004991	92.90	gold quality
dorsal plus ventral thalamus	UBERON:0001897	92.74	gold quality
superior vestibular nucleus	UBERON:0007227	92.73	gold quality
skin of abdomen	UBERON:0001416	92.69	gold quality
muscle of leg	UBERON:0001383	92.68	gold quality
left testis	UBERON:0004533	92.68	gold quality
cerebellum	UBERON:0002037	92.54	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.40

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

91 targeting TMEM63B, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4447	99.85	67.81	2900

Literature-anchored findings (GeneRIF, showing 2)

• overexpression of TMEM63B in HEK293T cells significantly enhanced cell migration and wound healing. (PMID:31243992)
• Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration. (PMID:37421948)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:153431	ENSDARG00000103608
danio_rerio	tmem63ba	ENSDARG00000104559
danio_rerio	tmem63bb	ENSDARG00000106631
mus_musculus	Tmem63b	ENSMUSG00000036026
rattus_norvegicus	Tmem63b	ENSRNOG00000019743

Paralogs (2): TMEM63C (ENSG00000165548), TMEM63A (ENSG00000196187)

Protein

Protein identifiers

Mechanosensitive cation channel TMEM63B — Q5T3F8 (reviewed: Q5T3F8)

Alternative names: Transmembrane protein 63B

All UniProt accessions (5): Q5T3F8, E9PNG1, H0YCP6, H0YDJ6, H3BLW6

UniProt curated annotations — full annotation on UniProt →

Function. Mechanosensitive cation channel with low conductance and high activation threshold. Osmosensitive cation channel preferentially activated by hypotonic stress. Also acts as a phospholipid scramblase in response to changes in membrane structure: upon changes in membrane curvature and thickness, alters its conformation and translocates phospholipids, such as phosphatidylcholine and sphingomyelin, thereby controlling plasma membrane lipid distribution. Forms a heterodimer with SLC19A2, which mediates phospholipid scramblase activity following Ca(2+) stimulation. Expressed in excitatory neurons of the subfornical organ and functions as a thirst receptor that mediates neuronal response to hyperosmolality to drive thirst and drinking behavior. Facilitates intestinal motility by promoting proliferation of intestinal stem cells. Essential 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. Acts as an osmosensor in cochlear outer hair cells (OHCs) where it mediates calcium influx and regulatory volume decrease response. Required for the maintenance of OHC morphology, OHC survival and normal hearing.

Subunit / interactions. Monomer. Interacts with SLC19A2; interaction is required for the phospholipid scramblase activity.

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

Post-translational modifications. Palmitoylation is required for localization to the plasma membrane and stability. N-Glycosylated.

Disease relevance. Developmental and epileptic encephalopathy 118 (DEE118) [MIM:621250] A form of epileptic encephalopathy, a heterogeneous group of early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE118 is an autosomal dominant form characterized by early-onset refractory epilepsy, severe global developmental delay, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes. The disease is caused by variants affecting the gene represented in this entry.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q5T3F8-1	1	yes
Q5T3F8-2	2
Q5T3F8-3	3

RefSeq proteins (2): NP_001305721, NP_060896* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003864	CSC1/OSCA1-like_7TM	Domain
IPR027815	CSC1/OSCA1-like_cyt	Domain
IPR032880	CSC1/OSCA1-like_N	Domain
IPR045122	Csc1-like	Family

Pfam: PF02714, PF13967, PF14703

Catalyzed reactions (Rhea), 7 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
• Mg(2+)(in) = Mg(2+)(out) (RHEA:29827)
• Na(+)(in) = Na(+)(out) (RHEA:34963)
• a 1,2-diacyl-sn-glycero-3-phosphocholine(in) = a 1,2-diacyl-sn-glycero-3-phosphocholine(out) (RHEA:38571)
• a sphingomyelin(in) = a sphingomyelin(out) (RHEA:39727)
• Cs(+)(in) = Cs(+)(out) (RHEA:78555)

UniProt features (57 total): topological domain 12, transmembrane region 11, sequence variant 11, lipid moiety-binding region 6, modified residue 4, splice variant 4, region of interest 3, chain 1, short sequence motif 1, compositionally biased region 1, glycosylation site 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8EHX	ELECTRON MICROSCOPY	3.6
8XW4	ELECTRON MICROSCOPY	3.84

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5T3F8-F1	73.16	0.28

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 (10): 111, 113, 114, 115, 51, 126, 382, 398, 726, 729

Glycosylation sites (1): 462

Mutagenesis-validated functional residues (1):

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

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 150 (showing top): GOBP_BEHAVIOR, GOCC_VACUOLAR_MEMBRANE, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOCC_SECRETORY_GRANULE, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_MEMBRANE_LIPID_DISTRIBUTION, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, GOBP_EXOCYTOSIS, GOBP_SECRETION, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, GOBP_SENSORY_PERCEPTION, GOBP_PHOSPHOLIPID_TRANSPORT

GO Biological Process (11): exocytosis (GO:0006887), sensory perception of sound (GO:0007605), intestinal stem cell homeostasis (GO:0036335), drinking behavior (GO:0042756), surfactant secretion (GO:0160069), monoatomic ion transport (GO:0006811), phospholipid transport (GO:0015914), plasma membrane phospholipid scrambling (GO:0017121), monoatomic ion transmembrane transport (GO:0034220), monoatomic cation transmembrane transport (GO:0098655), intermembrane lipid transfer (GO:0120009)

GO Molecular Function (7): calcium-activated cation channel activity (GO:0005227), mechanosensitive monoatomic ion channel activity (GO:0008381), phospholipid scramblase activity (GO:0017128), phosphatidylcholine transfer activity (GO:0120019), mechanosensitive monoatomic cation channel activity (GO:0140135), sphingomyelin transfer activity (GO:0140338), osmolarity-sensing monoatomic cation channel activity (GO:1990760)

GO Cellular Component (10): lysosomal membrane (GO:0005765), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), actin cytoskeleton (GO:0015629), early endosome membrane (GO:0031901), alveolar lamellar body membrane (GO:0097233), lysosome (GO:0005764), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipid transport	2
gated channel activity	2
phospholipid transfer activity	2
monoatomic cation channel activity	2
endomembrane system	2
vesicle-mediated transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
sensory perception of mechanical stimulus	1
homeostasis of number of cells	1
feeding behavior	1
surfactant homeostasis	1
secretion	1
transport	1
organophosphate ester transport	1
plasma membrane organization	1
phospholipid translocation	1
monoatomic ion transport	1
transmembrane transport	1
monoatomic cation transport	1
monoatomic ion transmembrane transport	1
membrane organization	1
monoatomic ion-gated channel activity	1
ligand-gated monoatomic cation channel activity	1
monoatomic ion channel activity	1
plasma membrane phospholipid scrambling	1
intramembrane lipid carrier activity	1
phosphatidylcholine binding	1
mechanosensitive monoatomic ion channel activity	1
sphingolipid transfer activity	1
osmosensor activity	1
lysosome	1
lytic vacuole membrane	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
cytoskeleton	1
early endosome	1

Protein interactions and networks

STRING

912 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM63B	CYFIP2	Q96F07	570
TMEM63B	AZIN1	O14977	489
TMEM63B	COG3	Q96JB2	488
TMEM63B	XKR6	Q5GH73	478
TMEM63B	GRIA3	P42263	464
TMEM63B	A0A1W2PNV4	A0A1W2PNV4	447
TMEM63B	TMEM234	Q8WY98	436
TMEM63B	UNC80	Q8N2C7	433
TMEM63B	TMEM147	Q9BVK8	432
TMEM63B	CCDC70	Q6NSX1	429
TMEM63B	ADARB1	P78555	429
TMEM63B	CADPS	Q9ULU8	429
TMEM63B	GRIK2	Q13002	424
TMEM63B	GRIA2	P42262	409
TMEM63B	TMEM120A	Q9BXJ8	405

IntAct

122 interactions, top by confidence:

A	B	Type	Score
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
ATP6V0A2	B4GALT3	psi-mi:“MI:0914”(association)	0.530
TMEM63B	SLC19A2	psi-mi:“MI:0914”(association)	0.530
YIPF3	TMEM120B	psi-mi:“MI:0914”(association)	0.530
SLC39A4	TMEM120B	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
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.530
SIDT2	AP3D1	psi-mi:“MI:0914”(association)	0.530
TMEM63A	AP3D1	psi-mi:“MI:0914”(association)	0.530
CXCR4	FANCA	psi-mi:“MI:0914”(association)	0.530
MARCKSL1	NMT2	psi-mi:“MI:0914”(association)	0.530
GPRC5B	STXBP3	psi-mi:“MI:0914”(association)	0.530
SLC30A2	ESYT2	psi-mi:“MI:0914”(association)	0.530
TMEM171	B3GAT3	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
TMEM63B	Tmem63b	psi-mi:“MI:0915”(physical association)	0.400
GPC1	SNAP23	psi-mi:“MI:0915”(physical association)	0.400
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
TMEM63B	MAPK14	psi-mi:“MI:0915”(physical association)	0.370
TMEM63B		psi-mi:“MI:0915”(physical association)	0.370
CHMP4B	ELOC	psi-mi:“MI:0914”(association)	0.350
TMEM63B	CAV1	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (186): TMEM63B (Affinity Capture-MS), TMEM63B (Affinity Capture-MS), TMEM63B (Affinity Capture-MS), ATP1A1 (Affinity Capture-MS), ATP2A2 (Affinity Capture-MS), ATP2B1 (Affinity Capture-MS), ATP5A1 (Affinity Capture-MS), ATP5B (Affinity Capture-MS), ATP5E (Affinity Capture-MS), ATP5I (Affinity Capture-MS), ATP6V1A (Affinity Capture-MS), ATP6V1B2 (Affinity Capture-MS), ATP5O (Affinity Capture-MS), CAV1 (Affinity Capture-MS), CD97 (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 151 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.

GO biological processes:

GO term	Partners	Fold	FDR
transport across blood-brain barrier	7	9.2×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	88
Likely benign	12
Benign	0

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
2579579	NM_018426.3(TMEM63B):c.1387G>A (p.Val463Ile)	Pathogenic
3458515	NM_018426.3(TMEM63B):c.1979G>C (p.Arg660Thr)	Pathogenic
3910004	NM_018426.3(TMEM63B):c.1442C>A (p.Thr481Asn)	Pathogenic
4083433	NM_018426.3(TMEM63B):c.1678G>C (p.Val560Leu)	Pathogenic
2580897	NM_018426.3(TMEM63B):c.1429C>G (p.Gln477Glu)	Likely pathogenic

SpliceAI

3736 predictions. Top by Δscore:

Variant	Effect	Δscore
6:44134739:TCCTT:T	donor_gain	1.0000
6:44134740:CCTT:C	donor_gain	1.0000
6:44134740:CCTTG:C	donor_loss	1.0000
6:44134741:CTT:C	donor_gain	1.0000
6:44134742:TT:T	donor_gain	1.0000
6:44134742:TTG:T	donor_loss	1.0000
6:44134743:TG:T	donor_loss	1.0000
6:44134744:G:C	donor_loss	1.0000
6:44134744:G:GG	donor_gain	1.0000
6:44134745:TAAG:T	donor_loss	1.0000
6:44135362:G:GT	donor_gain	1.0000
6:44135362:GAATA:G	donor_gain	1.0000
6:44135363:A:T	donor_gain	1.0000
6:44135365:TA:T	donor_gain	1.0000
6:44135367:G:GG	donor_gain	1.0000
6:44136347:A:AG	acceptor_gain	1.0000
6:44136347:AGTGT:A	acceptor_gain	1.0000
6:44136348:G:GA	acceptor_gain	1.0000
6:44136348:GT:G	acceptor_gain	1.0000
6:44136348:GTGT:G	acceptor_gain	1.0000
6:44136348:GTGTG:G	acceptor_gain	1.0000
6:44136436:CAATG:C	donor_loss	1.0000
6:44136437:AATGT:A	donor_loss	1.0000
6:44136438:AT:A	donor_gain	1.0000
6:44136438:ATG:A	donor_loss	1.0000
6:44136439:TGTG:T	donor_loss	1.0000
6:44136440:G:GG	donor_gain	1.0000
6:44136440:GTGA:G	donor_loss	1.0000
6:44136441:TGAG:T	donor_loss	1.0000
6:44136442:GA:G	donor_loss	1.0000

AlphaMissense

5475 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:44135066:G:A	G70E	1.000
6:44138492:T:A	W128R	1.000
6:44138492:T:C	W128R	1.000
6:44139590:C:A	N177K	1.000
6:44139590:C:G	N177K	1.000
6:44141041:T:A	L242H	1.000
6:44141041:T:C	L242P	1.000
6:44146870:T:A	V269D	1.000
6:44148351:T:C	F363L	1.000
6:44148352:T:C	F363S	1.000
6:44148353:T:A	F363L	1.000
6:44148353:T:G	F363L	1.000
6:44148355:T:A	V364D	1.000
6:44148610:T:A	W407R	1.000
6:44148610:T:C	W407R	1.000
6:44148792:G:C	W420C	1.000
6:44148792:G:T	W420C	1.000
6:44148884:C:A	P451Q	1.000
6:44148884:C:G	P451R	1.000
6:44150268:T:C	L522P	1.000
6:44151926:T:C	L585P	1.000
6:44152617:G:C	G621R	1.000
6:44152668:A:C	S638R	1.000
6:44152670:T:A	S638R	1.000
6:44152670:T:G	S638R	1.000
6:44134702:G:C	G40R	0.999
6:44134702:G:T	G40C	0.999
6:44134718:T:C	L45P	0.999
6:44135032:T:C	F59L	0.999
6:44135034:C:A	F59L	0.999

dbSNP variants (sampled 300 via entrez): RS1000334238 (6:44141010 C>T), RS1000339022 (6:44128132 T>C), RS1000386577 (6:44141246 G>A,C), RS1000549829 (6:44146495 G>T), RS1000770792 (6:44126696 A>T), RS1000893073 (6:44132870 C>A,T), RS1000898375 (6:44146037 G>A), RS1000962459 (6:44152713 G>A,C,T), RS1000985567 (6:44139041 C>G), RS1001190451 (6:44129897 T>C), RS1001494382 (6:44146347 T>C), RS1001509667 (6:44141408 C>A), RS1001589851 (6:44151606 G>A), RS1001643598 (6:44135913 A>C,G), RS1001717022 (6:44136101 C>A)

Disease associations

OMIM: gene MIM:619952 | disease phenotypes: MIM:621250

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Strong	Autosomal dominant
genetic developmental and epileptic encephalopathy	Strong	Autosomal dominant
TMEM63B-related developmental and epileptic encephalopathy with anemia	Moderate	Autosomal dominant

Mondo (4): developmental and epileptic encephalopathy 118 (MONDO:0979238), complex neurodevelopmental disorder (MONDO:0100038), genetic developmental and epileptic encephalopathy (MONDO:0100062), TMEM63B-related developmental and epileptic encephalopathy with anemia (MONDO:0800503)

Orphanet (1): Rare epilepsy (Orphanet:101998)

HPO phenotypes

67 total (30 of 67 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000076	Vesicoureteral reflux
HP:0000252	Microcephaly
HP:0000505	Visual impairment
HP:0000556	Retinal dystrophy
HP:0000639	Nystagmus
HP:0000729	Autistic behavior
HP:0000952	Jaundice
HP:0001082	Cholecystitis
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001337	Tremor
HP:0001357	Plagiocephaly
HP:0001371	Flexion contracture
HP:0001433	Hepatosplenomegaly
HP:0001596	Alopecia
HP:0001601	Laryngomalacia
HP:0001873	Thrombocytopenia
HP:0001903	Anemia
HP:0001915	Aplastic anemia
HP:0001923	Reticulocytosis
HP:0001972	Macrocytic anemia
HP:0002015	Dysphagia
HP:0002066	Gait ataxia
HP:0002069	Bilateral tonic-clonic seizure
HP:0002120	Cerebral cortical atrophy
HP:0002133	Status epilepticus

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005956_58	Waist-to-hip ratio adjusted for BMI	7.000000e-26
GCST005957_1	Waist-to-hip ratio adjusted for BMI (age <50)	2.000000e-14
GCST005958_2	Waist-to-hip ratio adjusted for BMI (age >50)	2.000000e-19
GCST005962_2	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	3.000000e-31

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Smoke	increases abundance, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	decreases methylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
monomethylarsonous acid	increases expression	1
nutlin 3	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Acetaminophen	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	decreases expression, increases abundance	1
Camptothecin	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Ribonucleotides	affects binding	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1
Acrylamide	decreases expression	1

Cellosaurus cell lines

2 cell lines: 1 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0RI	Ubigene HeLa TMEM63B KO	Cancer cell line	Female
CVCL_YA83	IDG-HEK293T-TMEM63B-V5-OE	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT05364021	PHASE1/PHASE2	COMPLETED	Study to Investigate LP352 in Subjects With Developmental and Epileptic Encephalopathies
NCT06983158	PHASE1/PHASE2	SUSPENDED	A Clinical Trial of CAP-002 Gene Therapy in Pediatric Patients With Syntaxin-Binding Protein 1 (STXBP1) Encephalopathy
NCT04937062	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy
NCT06149663	Not specified	AVAILABLE	Intermediate-Size Expanded Access Protocol (EAP) for LP352
NCT06380192	Not specified	RECRUITING	Developmental and Epileptic Encephalopathy of Genetic Etiology: Natural History Through Reuse of Clinical Data
NCT07396883	Not specified	NOT_YET_RECRUITING	Developmental and Epileptic Encephalopathies Diagnosed Via Long-read Genome Sequencing
NCT07531511	Not specified	NOT_YET_RECRUITING	SLC6A1-NDD Prospective Longitudinal Natural History Study
NCT07585643	Not specified	NOT_YET_RECRUITING	IBIS - Investigating Reliability of BIS and SEDLINE Monitoring in Children With Developmental and Epileptic Encephalopathies (DEE).