TMEM222

Summary

TMEM222 (transmembrane protein 222, HGNC:25363) is a protein-coding gene on chromosome 1p36.11, encoding Transmembrane protein 222 (Q9H0R3).

Located in dendrite.

Source: NCBI Gene 84065 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with motor and speech delay and behavioral abnormalities (Definitive, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 60 total — 5 pathogenic
• Phenotypes (HPO): 23
• MANE Select transcript: NM_032125

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25363
Approved symbol	TMEM222
Name	transmembrane protein 222
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP564D0478
Ensembl gene	ENSG00000186501
Ensembl biotype	protein_coding
OMIM	619469
Entrez	84065

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron

ENST00000374076, ENST00000464720, ENST00000464813, ENST00000466759, ENST00000470223, ENST00000471456, ENST00000478104, ENST00000486082, ENST00000498220, ENST00000608611, ENST00000611517, ENST00000915855, ENST00000915856

RefSeq mRNA: 1 — MANE Select: NM_032125 NM_032125

CCDS: CCDS297

Canonical transcript exons

ENST00000374076 — 6 exons

Exon	Start	End
ENSE00001694462	27330720	27330804
ENSE00001885171	27322163	27322391
ENSE00003523963	27332070	27332101
ENSE00003563279	27334151	27334281
ENSE00003666074	27333958	27334054
ENSE00003689854	27335379	27336400

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 94.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.3518 / max 137.9068, expressed in 1815 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1698	28.3992	1815
1697	0.9526	630

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hypothalamus	UBERON:0001898	94.16	gold quality
right frontal lobe	UBERON:0002810	93.99	gold quality
amygdala	UBERON:0001876	93.88	gold quality
putamen	UBERON:0001874	93.86	gold quality
nucleus accumbens	UBERON:0001882	93.86	gold quality
adenohypophysis	UBERON:0002196	93.81	gold quality
cingulate cortex	UBERON:0003027	93.80	gold quality
anterior cingulate cortex	UBERON:0009835	93.80	gold quality
apex of heart	UBERON:0002098	93.74	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.65	gold quality
cerebellar hemisphere	UBERON:0002245	93.36	gold quality
cerebellar cortex	UBERON:0002129	93.34	gold quality
pituitary gland	UBERON:0000007	93.28	gold quality
caudate nucleus	UBERON:0001873	93.27	gold quality
prefrontal cortex	UBERON:0000451	93.15	gold quality
ventral tegmental area	UBERON:0002691	93.09	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.04	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.04	gold quality
right uterine tube	UBERON:0001302	92.99	gold quality
cerebellar vermis	UBERON:0004720	92.98	silver quality
cerebellum	UBERON:0002037	92.96	gold quality
cranial nerve II	UBERON:0000941	92.91	gold quality
substantia nigra pars reticulata	UBERON:0001966	92.88	gold quality
spinal cord	UBERON:0002240	92.88	gold quality
type B pancreatic cell	CL:0000169	92.82	gold quality
granulocyte	CL:0000094	92.81	gold quality
CA1 field of hippocampus	UBERON:0003881	92.64	gold quality
lower esophagus mucosa	UBERON:0035834	92.57	gold quality
frontal cortex	UBERON:0001870	92.53	gold quality
neocortex	UBERON:0001950	92.53	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.16
E-MTAB-6386	no	379.39

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

43 targeting TMEM222, 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-6798-5P	100.00	65.77	699
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-4722-3P	99.35	65.22	1099
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-6761-5P	98.71	68.03	1504
HSA-MIR-3135B	98.61	65.33	1470

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem222a	ENSDARG00000069589
danio_rerio	tmem222b	ENSDARG00000104097
mus_musculus	Tmem222	ENSMUSG00000028857
rattus_norvegicus	Tmem222	ENSRNOG00000008564
drosophila_melanogaster	CG8372	FBGN0032000
caenorhabditis_elegans		WBGENE00019221

Protein

Protein identifiers

Transmembrane protein 222 — Q9H0R3 (reviewed: Q9H0R3)

All UniProt accessions (7): H0Y861, H0Y870, H0Y8D0, H7C5C5, Q5SSC2, Q9H0R3, Q8TDQ4

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Membrane. Cell projection. Dendrite.

Tissue specificity. Widely expressed. The highest expression is observed in the brain.

Disease relevance. Neurodevelopmental disorder with motor and speech delay and behavioral abnormalities (NEDMOSBA) [MIM:619470] An autosomal recessive disorder characterized by global developmental delay, impaired intellectual development, speech delay, delayed walking, and behavioral abnormalities. Some patients develop spastic tetraplegia with inability to walk independently and never gain proper speech. Affected individuals may have variable additional features, including poor overall growth, hypotonia, tremor, ocular anomalies, seizures, and non-specific dysmorphic facial features. The disease may be caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H0R3-1	1	yes
Q9H0R3-2	2

RefSeq proteins (1): NP_115501* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008496	TMEM222/RTE1	Family

Pfam: PF05608

UniProt features (16 total): sequence variant 5, topological domain 4, transmembrane region 3, chain 1, sequence conflict 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H0R3-F1	85.70	0.71

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 162 (showing top): FREAC3_01, MARTINEZ_RB1_TARGETS_DN, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_AND_BRAIN_QTL_TRANS, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, GOCC_NEURON_PROJECTION, LEE_LIVER_CANCER_E2F1_DN, MARTINEZ_RB1_AND_TP53_TARGETS_UP, ETF_Q6, ZHENG_BOUND_BY_FOXP3, MARSON_BOUND_BY_FOXP3_UNSTIMULATED, GOCC_SOMATODENDRITIC_COMPARTMENT, SCGGAAGY_ELK1_02, ATGGYGGA_UNKNOWN, JIANG_VHL_TARGETS, chr1p36

GO Biological Process (0):

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): membrane (GO:0016020), dendrite (GO:0030425), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
binding	1
neuron projection	1
dendritic tree	1

Protein interactions and networks

STRING

450 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM222	SMAGP	Q0VAQ4	476
TMEM222	SURF6	O75683	461
TMEM222	UBTD1	Q9HAC8	418
TMEM222	TMEM161B	Q8NDZ6	404
TMEM222	PDRG1	Q9NUG6	394
TMEM222	MED10	Q9BTT4	391
TMEM222	SYT16	Q17RD7	391
TMEM222	C1QTNF12	Q5T7M4	348
TMEM222	LGI2	Q8N0V4	348
TMEM222	TRMT6	Q9UJA5	346
TMEM222	TTLL10	Q6ZVT0	325
TMEM222	MPC2	O95563	324
TMEM222	CUEDC2	Q9H467	318
TMEM222	SMG7	Q92540	315
TMEM222	NSMAF	Q92636	311

IntAct

115 interactions, top by confidence:

A	B	Type	Score
GNAI3	RGS12	psi-mi:“MI:0914”(association)	0.640
TMEM222	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
TMEM222	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
TMEM222	HIBADH	psi-mi:“MI:0915”(physical association)	0.560
TMEM222	TMX2	psi-mi:“MI:0915”(physical association)	0.560
TMEM222	EVI2B	psi-mi:“MI:0915”(physical association)	0.560
STX1A	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
TMPRSS2	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
LRRC59	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
BIK	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
CREB3L1	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
BSCL2	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
CD79A	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
FAM209A	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
SLC10A1	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
RNASEK	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
PTGES	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
FAM174A	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
NCR3LG1	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
COMT	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
ELOVL4	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
TMEM35A	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
KIR2DL3	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
TMEM222	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
HSD17B13	TMEM222	psi-mi:“MI:0915”(physical association)	0.560
TMEM222	ERG28	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (58): TMEM222 (Affinity Capture-RNA), TMEM222 (Affinity Capture-RNA), TMEM222 (Affinity Capture-MS), TMEM222 (Two-hybrid), TMEM222 (Proximity Label-MS), TMEM222 (Two-hybrid), TMEM222 (Affinity Capture-MS), TMEM222 (Affinity Capture-MS), TMEM222 (Affinity Capture-MS), TMEM222 (Affinity Capture-MS), TMEM222 (Two-hybrid), TMEM222 (Two-hybrid), TMEM222 (Two-hybrid), TMEM222 (Two-hybrid), TMEM222 (Two-hybrid)

ESM2 similar proteins: A0A0R4IY06, A0JPF9, A0JPH4, A2AQW0, A5PKL6, A7MBC7, D2KX21, E1BCH6, E9PYK3, F1ND48, F4IVI0, O14524, O35099, O95237, Q14680, Q149N8, Q1RMU2, Q498D5, Q4R6Y8, Q502W6, Q5R5S1, Q5RDB4, Q5RED8, Q5RL51, Q61846, Q66H62, Q6NTT6, Q6ZN16, Q6ZQE4, Q7TPQ3, Q80TQ2, Q811C2, Q8BSE0, Q8BVA2, Q8K2I9, Q8NE18, Q8NEC7, Q93V51, Q96DT6, Q96KN1

Diamond homologs: F4ITL6, Q8BVA2, Q9H0R3, Q9SD42

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	0
Uncertain significance	37
Likely benign	6
Benign	2

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1195879	NM_032125.3(TMEM222):c.535_537del (p.Val179del)	Pathogenic
1195880	NM_032125.3(TMEM222):c.214G>A (p.Gly72Ser)	Pathogenic
1195881	NM_032125.3(TMEM222):c.539+2T>C	Pathogenic
1195882	NM_032125.3(TMEM222):c.207dup (p.Ile70fs)	Pathogenic
1195883	NM_032125.3(TMEM222):c.334C>T (p.Gln112Ter)	Pathogenic

SpliceAI

1082 predictions. Top by Δscore:

Variant	Effect	Δscore
1:27322392:G:GG	donor_gain	1.0000
1:27330718:AGGT:A	acceptor_gain	1.0000
1:27330719:GGTG:G	acceptor_gain	1.0000
1:27330805:G:GG	donor_gain	1.0000
1:27332064:CAACA:C	acceptor_loss	1.0000
1:27332068:A:AG	acceptor_gain	1.0000
1:27332068:A:T	acceptor_loss	1.0000
1:27332069:G:GG	acceptor_gain	1.0000
1:27332102:G:GG	donor_gain	1.0000
1:27333955:CAG:C	acceptor_loss	1.0000
1:27333956:AGGT:A	acceptor_loss	1.0000
1:27334050:GCATG:G	donor_gain	1.0000
1:27334052:ATGG:A	donor_loss	1.0000
1:27334053:TGGT:T	donor_loss	1.0000
1:27334054:GGTA:G	donor_loss	1.0000
1:27334055:G:GC	donor_loss	1.0000
1:27334055:G:GG	donor_gain	1.0000
1:27334056:T:A	donor_loss	1.0000
1:27334145:CTCCA:C	acceptor_loss	1.0000
1:27334146:TCCA:T	acceptor_loss	1.0000
1:27334147:CCAGC:C	acceptor_loss	1.0000
1:27334148:CAGC:C	acceptor_loss	1.0000
1:27334149:A:AC	acceptor_loss	1.0000
1:27334149:A:AG	acceptor_gain	1.0000
1:27334150:G:GT	acceptor_gain	1.0000
1:27334150:GC:G	acceptor_gain	1.0000
1:27334150:GCA:G	acceptor_gain	1.0000
1:27334150:GCAC:G	acceptor_gain	1.0000
1:27334150:GCACA:G	acceptor_gain	1.0000
1:27334270:G:GT	donor_gain	1.0000

AlphaMissense

1374 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:27330740:G:A	G72D	1.000
1:27330756:C:G	C77W	1.000
1:27330779:A:C	D85A	1.000
1:27330779:A:T	D85V	1.000
1:27330781:T:C	F86L	1.000
1:27330782:T:C	F86S	1.000
1:27330782:T:G	F86C	1.000
1:27330783:C:A	F86L	1.000
1:27330783:C:G	F86L	1.000
1:27332085:T:C	F99L	1.000
1:27332087:T:A	F99L	1.000
1:27332087:T:G	F99L	1.000
1:27334171:C:A	N143K	1.000
1:27334171:C:G	N143K	1.000
1:27322369:T:A	W58R	0.999
1:27322369:T:C	W58R	0.999
1:27322379:T:C	I61T	0.999
1:27330739:G:C	G72R	0.999
1:27330740:G:T	G72V	0.999
1:27330742:C:G	H73D	0.999
1:27330744:C:A	H73Q	0.999
1:27330744:C:G	H73Q	0.999
1:27330748:G:C	G75R	0.999
1:27330755:G:A	C77Y	0.999
1:27330767:G:A	G81E	0.999
1:27330767:G:T	G81V	0.999
1:27330776:G:C	R84P	0.999
1:27330778:G:C	D85H	0.999
1:27330779:A:G	D85G	0.999
1:27330781:T:A	F86I	0.999

dbSNP variants (sampled 300 via entrez): RS1000068306 (1:27327431 C>T), RS1000497048 (1:27328118 G>A), RS1001073219 (1:27322724 T>G), RS1001334177 (1:27323859 T>C), RS1001397809 (1:27325109 G>A,T), RS1001495617 (1:27326726 A>T), RS1001557058 (1:27336879 G>A,T), RS1001722201 (1:27331861 C>T), RS1001820169 (1:27331525 T>C), RS1001885127 (1:27333331 C>T), RS1002106799 (1:27329899 C>T), RS1002494678 (1:27331887 G>A,T), RS1002506637 (1:27325490 C>G), RS1002617570 (1:27325670 G>A), RS1002947996 (1:27322486 C>A,G,T)

Disease associations

OMIM: gene MIM:619469 | disease phenotypes: MIM:619470

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with motor and speech delay and behavioral abnormalities	Definitive	Autosomal recessive

Mondo (1): neurodevelopmental disorder with motor and speech delay and behavioral abnormalities (MONDO:0859176)

Orphanet (0):

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000486	Strabismus
HP:0000648	Optic atrophy
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001285	Spastic tetraparesis
HP:0001337	Tremor
HP:0001792	Small nail
HP:0002136	Broad-based gait
HP:0002987	Elbow flexion contracture
HP:0009879	Simplified gyral pattern
HP:0020045	Esodeviation
HP:0030891	Periventricular white matter hyperintensities
HP:0031936	Delayed ability to walk

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008173_2	Alanine aminotransferase levels	8.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	affects expression	1
cobaltous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	increases expression	1
Decitabine	affects expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1
Cisplatin	affects expression	1
Diethylstilbestrol	decreases expression	1
Nicotine	increases splicing	1
Quercetin	increases expression	1
Selenium	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases methylation	1
Vitamin E	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1

Clinical trials (associated diseases)

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