LRRC8C

Summary

LRRC8C (leucine rich repeat containing 8 VRAC subunit C, HGNC:25075) is a protein-coding gene on chromosome 1p22.2, encoding Volume-regulated anion channel subunit LRRC8C (Q8TDW0). Non-essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes.

Enables volume-sensitive anion channel activity. Involved in cyclic-GMP-AMP transmembrane import across plasma membrane and monoatomic anion transmembrane transport. Located in cytoplasm and plasma membrane.

Source: NCBI Gene 84230 — RefSeq curated summary.

At a glance

• Gene–disease (curated): telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 72 total — 2 pathogenic
• Phenotypes (HPO): 38
• MANE Select transcript: NM_032270

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25075
Approved symbol	LRRC8C
Name	leucine rich repeat containing 8 VRAC subunit C
Location	1p22.2
Locus type	gene with protein product
Status	Approved
Aliases	AD158
Ensembl gene	ENSG00000171488
Ensembl biotype	protein_coding
OMIM	612889
Entrez	84230

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 2 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000370454, ENST00000416805, ENST00000479252, ENST00000482063, ENST00000856739

RefSeq mRNA: 1 — MANE Select: NM_032270 NM_032270

CCDS: CCDS725

Canonical transcript exons

ENST00000370454 — 3 exons

Exon	Start	End
ENSE00001452754	89712709	89719533
ENSE00003702077	89686470	89686611
ENSE00003845612	89633120	89633322

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 93.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.4342 / max 273.3259, expressed in 1624 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
3968	10.8071	1559
3965	1.2315	391
3969	0.8376	273
3966	0.8240	449
3967	0.6914	418
201572	0.0427	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	93.80	gold quality
secondary oocyte	CL:0000655	92.70	gold quality
cartilage tissue	UBERON:0002418	89.88	gold quality
oocyte	CL:0000023	88.93	gold quality
left ventricle myocardium	UBERON:0006566	87.83	gold quality
buccal mucosa cell	CL:0002336	87.43	gold quality
leukocyte	CL:0000738	87.23	gold quality
monocyte	CL:0000576	87.12	gold quality
lower lobe of lung	UBERON:0008949	85.33	gold quality
superficial temporal artery	UBERON:0001614	85.00	gold quality
heart right ventricle	UBERON:0002080	84.82	gold quality
myocardium	UBERON:0002349	84.52	silver quality
smooth muscle tissue	UBERON:0001135	83.90	gold quality
cardiac muscle of right atrium	UBERON:0003379	83.75	silver quality
granulocyte	CL:0000094	83.09	gold quality
subcutaneous adipose tissue	UBERON:0002190	82.72	gold quality
lymph node	UBERON:0000029	82.63	gold quality
adipose tissue	UBERON:0001013	82.32	gold quality
upper arm skin	UBERON:0004263	82.14	silver quality
visceral pleura	UBERON:0002401	82.09	gold quality
sural nerve	UBERON:0015488	81.69	gold quality
ileal mucosa	UBERON:0000331	81.24	gold quality
skin of hip	UBERON:0001554	81.23	gold quality
adipose tissue of abdominal region	UBERON:0007808	81.11	gold quality
parietal pleura	UBERON:0002400	81.06	gold quality
omental fat pad	UBERON:0010414	80.96	gold quality
peritoneum	UBERON:0002358	80.93	gold quality
vermiform appendix	UBERON:0001154	80.86	gold quality
bone marrow	UBERON:0002371	80.78	gold quality
blood	UBERON:0000178	80.30	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.47

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

188 targeting LRRC8C, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-1250-3P	99.96	70.04	4038

Literature-anchored findings (GeneRIF, showing 2)

• identified four genes, named TA-LRRP, AD158, LRRC5, and FLJ23420, as unknown LRRC8-like genes (PMID:15094057)
• fad158 has a role in regulating adipocyte differentiation (PMID:15184384)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrrc8c	ENSDARG00000099911
mus_musculus	Lrrc8c	ENSMUSG00000054720
rattus_norvegicus	Lrrc8c	ENSRNOG00000065000

Paralogs (31): LRRC7 (ENSG00000033122), PHLPP2 (ENSG00000040199), LRRC40 (ENSG00000066557), LRCH4 (ENSG00000077454), PHLPP1 (ENSG00000081913), SHOC2 (ENSG00000108061), ERBIN (ENSG00000112851), LRRC39 (ENSG00000122477), LRCH2 (ENSG00000130224), LRCH1 (ENSG00000136141), LRRC8A (ENSG00000136802), LRRC1 (ENSG00000137269), MFHAS1 (ENSG00000147324), LRRC27 (ENSG00000148814), LRRK1 (ENSG00000154237), LRRC58 (ENSG00000163428), LRRC2 (ENSG00000163827), LRRC18 (ENSG00000165383), LRRC28 (ENSG00000168904), LRRC8E (ENSG00000171017), LRRC8D (ENSG00000171492), PIDD1 (ENSG00000177595), SCRIB (ENSG00000180900), LRCH3 (ENSG00000186001), LRRIQ4 (ENSG00000188306), LRRC8B (ENSG00000197147), LRRC10 (ENSG00000198812), LRRC10B (ENSG00000204950), LRRC30 (ENSG00000206422), LRRC69 (ENSG00000214954), LRRD1 (ENSG00000240720)

Protein

Protein identifiers

Volume-regulated anion channel subunit LRRC8C — Q8TDW0 (reviewed: Q8TDW0)

Alternative names: Factor for adipocyte differentiation 158, Leucine-rich repeat-containing protein 8C

All UniProt accessions (2): Q8TDW0, E9PHY6

UniProt curated annotations — full annotation on UniProt →

Function. Non-essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes. The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine. Plays a redundant role in the efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress. The VRAC channel also mediates transport of immunoreactive cyclic dinucleotide GMP-AMP (2’-3’-cGAMP), an immune messenger produced in response to DNA virus in the cytosol. Channel activity requires LRRC8A plus at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition.

Subunit / interactions. Heterohexamer; oligomerizes with other LRRC8 proteins (LRRC8A, LRRC8B, LRRC8D and/or LRRC8E) to form a heterohexamer. Homoheptamer; inactive, likely because it is not targeted to the plasma membrane in the absence of LRRC8A. In vivo, the subunit composition may depend primarily on expression levels, and heterooligomeric channels containing various proportions of the different LRRC8 proteins may coexist.

Subcellular location. Cell membrane. Endoplasmic reticulum membrane.

Tissue specificity. Expressed at highest levels in skeletal muscle, and at moderate levels in heart, lung and peripheral blood leukocytes.

Disease relevance. Telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature (TIMES) [MIM:621056] An autosomal dominant, pleiotropic disorder characterized by variable features that include telangiectasia, gastrointestinal vascular dysplasia, intellectual disability, skeletal dysplasia with fragile bones, short stature, and eye abnormalities. Patients exhibit striking cutis marmorata in infancy. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The volume-regulated anion channel (VRAC) channel forms a trimer of dimers, with symmetry mismatch between the pore-forming domain and the cytosolic LRR repeats, a topology similar to gap junction proteins. The cytoplasmic N-terminus preceding the first transmembrane (residues 1-22) regulates volume-regulated anion channel (VRAC) conductance, ion permeability and inactivation gating.

Similarity. Belongs to the LRRC8 family.

RefSeq proteins (1): NP_115646* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR021040	LRRC8_Pannexin-like	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR050216	LRR_domain-containing	Family

Pfam: PF12534, PF13855

Catalyzed reactions (Rhea), 4 shown:

• chloride(in) = chloride(out) (RHEA:29823)
• 2’,3’-cGAMP(out) = 2’,3’-cGAMP(in) (RHEA:66320)
• iodide(out) = iodide(in) (RHEA:66324)
• taurine(out) = taurine(in) (RHEA:66328)

UniProt features (62 total): repeat 17, helix 13, topological domain 5, strand 5, transmembrane region 4, sequence variant 4, modified residue 2, glycosylation site 2, disulfide bond 2, mutagenesis site 2, turn 2, chain 1, region of interest 1, compositionally biased region 1, sequence conflict 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
8DXN	ELECTRON MICROSCOPY	3.4
9EZC	ELECTRON MICROSCOPY	3.41
8DXO	ELECTRON MICROSCOPY	3.6
8DXP	ELECTRON MICROSCOPY	3.7
8RTS	ELECTRON MICROSCOPY	3.73
8DXQ	ELECTRON MICROSCOPY	3.8
8DXR	ELECTRON MICROSCOPY	4
9F16	ELECTRON MICROSCOPY	4.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TDW0-F1	83.95	0.50

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 (2): 212, 215

Disulfide bonds (2): 54–308, 115–293

Glycosylation sites (2): 64, 70

Mutagenesis-validated functional residues (2):

Position	Phenotype
6	decreased amplitudes of swelling-activated current.
44	alters channel anion selectivity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5223345	Miscellaneous transport and binding events
R-HSA-382551	Transport of small molecules

MSigDB gene sets: 344 (showing top): HORIUCHI_WTAP_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_AMINO_ACID_TRANSMEMBRANE_TRANSPORT, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_NUCLEOTIDE_TRANSPORT, GOBP_ORGANIC_ACID_TRANSPORT, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, BILD_HRAS_ONCOGENIC_SIGNATURE, MARTINEZ_RB1_TARGETS_UP, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, FOSTER_TOLERANT_MACROPHAGE_DN, MYOD_01, GOBP_NUCLEOTIDE_TRANSMEMBRANE_TRANSPORT, GOBP_AMINO_ACID_TRANSPORT

GO Biological Process (10): taurine transmembrane transport (GO:0015734), aspartate transmembrane transport (GO:0015810), protein hexamerization (GO:0034214), fat cell differentiation (GO:0045444), cellular response to osmotic stress (GO:0071470), monoatomic anion transmembrane transport (GO:0098656), cyclic-GMP-AMP transmembrane import across plasma membrane (GO:0140361), RNA processing (GO:0006396), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (2): volume-sensitive anion channel activity (GO:0005225), protein binding (GO:0005515)

GO Cellular Component (7): cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702), nucleolus (GO:0005730), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nitrogen compound transport	2
cellular anatomical structure	2
alkanesulfonate transmembrane transport	1
amino acid transmembrane transport	1
C4-dicarboxylate transport	1
acidic amino acid transport	1
carboxylic acid transmembrane transport	1
protein complex oligomerization	1
cell differentiation	1
response to osmotic stress	1
cellular response to chemical stress	1
cellular response to abiotic stimulus	1
monoatomic anion transport	1
monoatomic ion transmembrane transport	1
purine ribonucleotide transport	1
adenine nucleotide transport	1
cyclic nucleotide transport	1
import across plasma membrane	1
guanine nucleotide transmembrane transport	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
transport	1
monoatomic ion transport	1
transmembrane transport	1
monoatomic anion channel activity	1
binding	1
intracellular anatomical structure	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
transmembrane transporter complex	1
nuclear lumen	1
intracellular membraneless organelle	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

958 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRRC8C	TTYH2	Q9BSA4	664
LRRC8C	FABP4	P15090	639
LRRC8C	TTYH3	Q9C0H2	625
LRRC8C	BEST1	O76090	559
LRRC8C	LPL	P06858	548
LRRC8C	TTYH1	Q9H313	545
LRRC8C	SREBF1	P36956	541
LRRC8C	CLCN3	P51790	528
LRRC8C	LRRC8A	Q8IWT6	525
LRRC8C	HEPACAM	Q14CZ8	507
LRRC8C	KCP	Q6ZWJ8	501
LRRC8C	CLCA4	Q14CN2	478
LRRC8C	CLCA2	Q9UQC9	473
LRRC8C	CFTR	P13569	442
LRRC8C	BSND	Q8WZ55	433

IntAct

33 interactions, top by confidence:

A	B	Type	Score
ZACN	GPAA1	psi-mi:“MI:0914”(association)	0.530
LRRC8B	SLC25A17	psi-mi:“MI:0914”(association)	0.530
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
SIDT2	AP3D1	psi-mi:“MI:0914”(association)	0.530
LRRC8A	LRRC8C	psi-mi:“MI:0915”(physical association)	0.400
LGALS8	SLC22A23	psi-mi:“MI:0914”(association)	0.350
FPR2	GPR89A	psi-mi:“MI:0914”(association)	0.350
HTR3A	GPAA1	psi-mi:“MI:0914”(association)	0.350
FCGR3B	NRP2	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
SCAMP2	SCAMP1	psi-mi:“MI:0914”(association)	0.350
NCLN	PGRMC1	psi-mi:“MI:0914”(association)	0.350
KCNA2	TMEM129	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
TSPAN15	TMEM223	psi-mi:“MI:0914”(association)	0.350
HCST	TMEM120B	psi-mi:“MI:0914”(association)	0.350
ZACN	FAM234B	psi-mi:“MI:0914”(association)	0.350
SIDT2	KLRG2	psi-mi:“MI:0914”(association)	0.350
MS4A15	ABCD4	psi-mi:“MI:0914”(association)	0.350
OR10H2	ABCD4	psi-mi:“MI:0914”(association)	0.350
HTR3A	EXTL3	psi-mi:“MI:0914”(association)	0.350
NPEPPS	KIF5B	psi-mi:“MI:0914”(association)	0.350
POPDC2	ANK2	psi-mi:“MI:0914”(association)	0.350
LRRC8B	CDH2	psi-mi:“MI:0914”(association)	0.350

BioGRID (62): LRRC8C (Affinity Capture-MS), LRRC8C (Affinity Capture-MS), LRRC8C (Affinity Capture-MS), LRRC8C (Affinity Capture-MS), LRRC8C (Affinity Capture-MS), LRRC8C (Affinity Capture-MS), LRRC8C (Affinity Capture-MS), LRRC8C (Affinity Capture-MS), LRRC8C (Affinity Capture-MS), LRRC8C (Affinity Capture-MS), LRRC8C (Affinity Capture-MS), LRRC8C (Affinity Capture-RNA), LRRC8C (Proximity Label-MS), LRRC8C (Proximity Label-MS), LRRC8C (Proximity Label-MS)

ESM2 similar proteins: A0JM56, A0JPI9, A2BFL2, A5PK13, A6H639, J9SQF3, O13066, P19686, P33402, Q02108, Q0VAA2, Q14BP6, Q15111, Q15813, Q3USB7, Q498T9, Q4R642, Q4V8D9, Q4ZHS0, Q5DU41, Q5FVQ9, Q5RAG3, Q5RBD9, Q5RJH2, Q5ZIJ9, Q5ZIU8, Q62688, Q68F79, Q6DN12, Q6GQN5, Q6NU09, Q6P9F7, Q6WRX3, Q7Z7L7, Q80ZJ6, Q8BG40, Q8CDU4, Q8CIR4, Q8CIV8, Q8HXA6

Diamond homologs: A5PK13, Q3KRC6, Q498T9, Q4V8I7, Q5DU41, Q5U308, Q66JT1, Q68F79, Q6NSJ5, Q6NU09, Q6P9F7, Q7L1W4, Q80WG5, Q8BGR2, Q8IWT6, Q8R502, Q8TDW0, A6NIV6, Q9Z1S7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	65
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3393525	NM_032270.5(LRRC8C):c.1197dup (p.Leu400fs)	Pathogenic
3393526	NM_032270.5(LRRC8C):c.1168G>C (p.Val390Leu)	Pathogenic

SpliceAI

1828 predictions. Top by Δscore:

Variant	Effect	Δscore
1:89712700:AT:A	acceptor_gain	1.0000
1:89712703:TTTCA:T	acceptor_loss	1.0000
1:89712704:TTCA:T	acceptor_loss	1.0000
1:89712705:TCAGG:T	acceptor_loss	1.0000
1:89712706:CAG:C	acceptor_loss	1.0000
1:89712706:CAGGT:C	acceptor_loss	1.0000
1:89712707:A:C	acceptor_loss	1.0000
1:89633319:GGAG:G	donor_gain	0.9900
1:89633320:G:GT	donor_gain	0.9900
1:89633320:GAG:G	donor_gain	0.9900
1:89633320:GAGG:G	donor_gain	0.9900
1:89633321:AGG:A	donor_loss	0.9900
1:89633323:G:C	donor_loss	0.9900
1:89633324:T:A	donor_loss	0.9900
1:89684602:C:G	donor_gain	0.9900
1:89686465:CTCA:C	acceptor_loss	0.9900
1:89686466:TCAG:T	acceptor_loss	0.9900
1:89686467:CAG:C	acceptor_loss	0.9900
1:89686468:A:AG	acceptor_gain	0.9900
1:89686468:A:T	acceptor_loss	0.9900
1:89686469:G:GA	acceptor_gain	0.9900
1:89686469:G:GG	acceptor_gain	0.9900
1:89686469:GAAAC:G	acceptor_gain	0.9900
1:89686607:TACAG:T	donor_loss	0.9900
1:89686608:ACAG:A	donor_loss	0.9900
1:89686609:CAG:C	donor_loss	0.9900
1:89686610:AG:A	donor_loss	0.9900
1:89686610:AGGTA:A	donor_loss	0.9900
1:89686611:GG:G	donor_loss	0.9900
1:89686612:GT:G	donor_loss	0.9900

AlphaMissense

5333 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:89686543:T:A	W24R	1.000
1:89686543:T:C	W24R	1.000
1:89712730:T:A	C54S	1.000
1:89712730:T:C	C54R	1.000
1:89712731:G:A	C54Y	1.000
1:89712731:G:C	C54S	1.000
1:89712732:C:G	C54W	1.000
1:89712913:T:A	C115S	1.000
1:89712913:T:C	C115R	1.000
1:89712914:G:A	C115Y	1.000
1:89712914:G:C	C115S	1.000
1:89712915:T:G	C115W	1.000
1:89713078:T:A	W170R	1.000
1:89713078:T:C	W170R	1.000
1:89713080:G:C	W170C	1.000
1:89713080:G:T	W170C	1.000
1:89713447:T:C	C293R	1.000
1:89713492:T:A	C308S	1.000
1:89713493:G:A	C308Y	1.000
1:89713493:G:C	C308S	1.000
1:89713494:C:G	C308W	1.000
1:89713741:T:C	F391L	1.000
1:89713742:T:C	F391S	1.000
1:89713743:C:A	F391L	1.000
1:89713743:C:G	F391L	1.000
1:89713748:C:T	S393F	1.000
1:89713769:T:C	L400S	1.000
1:89686538:C:A	P22Q	0.999
1:89686545:G:C	W24C	0.999
1:89686545:G:T	W24C	0.999

dbSNP variants (sampled 300 via entrez): RS1000016118 (1:89661107 A>G), RS1000064819 (1:89695645 G>A), RS1000069174 (1:89675502 C>T), RS1000109059 (1:89632864 G>A,C), RS1000112539 (1:89623505 A>G), RS1000116041 (1:89711899 A>G), RS1000128025 (1:89651361 G>A,T), RS1000160331 (1:89702710 C>A), RS1000188107 (1:89613962 C>G,T), RS1000225001 (1:89702378 C>T), RS1000289589 (1:89702058 C>T), RS1000346963 (1:89664758 A>G), RS1000348587 (1:89651602 C>T), RS1000361237 (1:89644404 G>T), RS1000369076 (1:89708229 A>C)

Disease associations

OMIM: gene MIM:612889 | disease phenotypes: MIM:621056

GenCC curated gene-disease

Disease	Classification	Inheritance
telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature	Moderate	Autosomal dominant
neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (2): telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature (MONDO:0975957), neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

38 total (30 of 38 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000252	Microcephaly
HP:0000378	Cupped ear
HP:0000463	Anteverted nares
HP:0000483	Astigmatism
HP:0000490	Deeply set eye
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000545	Myopia
HP:0000563	Keratoconus
HP:0000582	Upslanted palpebral fissure
HP:0000601	Hypotelorism
HP:0000621	Entropion
HP:0000648	Optic atrophy
HP:0000750	Delayed speech and language development
HP:0000787	Nephrolithiasis
HP:0000821	Hypothyroidism
HP:0000822	Hypertension
HP:0000938	Osteopenia
HP:0000965	Cutis marmorata
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0002023	Anal atresia
HP:0002239	Gastrointestinal hemorrhage
HP:0002342	Moderate intellectual disability
HP:0002353	EEG abnormality
HP:0002604	Gastrointestinal telangiectasia
HP:0002757	Recurrent fractures
HP:0003196	Short nose

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002337_69	Amyotrophic lateral sclerosis (sporadic)	5.000000e-06
GCST006210_1	Thiopurine-induced digestive symptoms in inflammatory bowel disease	7.000000e-07
GCST006979_991	Heel bone mineral density	4.000000e-09
GCST009391_64	Metabolite levels	6.000000e-06
GCST90002395_311	Mean platelet volume	2.000000e-17

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0010352	diacylglycerol 34:1 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	4
trichostatin A	increases expression, affects cotreatment, decreases expression	3
entinostat	decreases expression, increases expression, affects cotreatment	2
Benzo(a)pyrene	decreases methylation, affects methylation	2
Cisplatin	affects cotreatment, decreases expression, increases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	increases methylation, decreases methylation	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
sodium arsenite	increases abundance, increases expression, affects cotreatment	1
cobaltous chloride	decreases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
benzo(e)pyrene	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
ICG 001	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Arsenic	increases expression, affects cotreatment, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice