IRS4

Summary

IRS4 (insulin receptor substrate 4, HGNC:6128) is a protein-coding gene on chromosome Xq22.3, encoding Insulin receptor substrate 4 (O14654). Acts as an interface between multiple growth factor receptors possessing tyrosine kinase activity, such as insulin receptor, IGF1R and FGFR1, and a complex network of intracellular signaling molecules containing SH2 domains.

IRS4 encodes the insulin receptor substrate 4, a cytoplasmic protein that contains many potential tyrosine and serine/threonine phosphorylation sites. Tyrosine-phosphorylated IRS4 protein has been shown to associate with cytoplasmic signalling molecules that contain SH2 domains. The IRS4 protein is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation..

Source: NCBI Gene 8471 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypothyroidism, congenital, nongoitrous, 9 (Strong, GenCC)
• Clinical variants (ClinVar): 168 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 7
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• MANE Select transcript: NM_001379150

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6128
Approved symbol	IRS4
Name	insulin receptor substrate 4
Location	Xq22.3
Locus type	gene with protein product
Status	Approved
Aliases	PY160, IRS-4
Ensembl gene	ENSG00000133124
Ensembl biotype	protein_coding
OMIM	300904
Entrez	8471

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000372129, ENST00000564206

RefSeq mRNA: 2 — MANE Select: NM_001379150 NM_001379150, NM_003604

CCDS: CCDS14544, CCDS94648

Canonical transcript exons

ENST00000372129 — 2 exons

Exon	Start	End
ENSE00001456960	108732579	108736563
ENSE00002599543	108719946	108722523

Expression profiles

Bgee: expression breadth broad, 38 present calls, max score 67.82.

FANTOM5 (CAGE): breadth broad, TPM avg 3.2962 / max 511.4145, expressed in 183 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200109	3.0153	150
200111	0.1733	105
200110	0.1076	56

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pituitary gland	UBERON:0000007	67.82	gold quality
adenohypophysis	UBERON:0002196	63.75	gold quality
ovary	UBERON:0000992	60.66	gold quality
left ovary	UBERON:0002119	60.58	gold quality
right ovary	UBERON:0002118	59.11	gold quality
mucosa of stomach	UBERON:0001199	59.02	gold quality
hypothalamus	UBERON:0001898	55.20	gold quality
body of uterus	UBERON:0009853	52.33	gold quality
right lobe of thyroid gland	UBERON:0001119	51.56	gold quality
thyroid gland	UBERON:0002046	51.42	gold quality
uterine cervix	UBERON:0000002	51.29	gold quality
left lobe of thyroid gland	UBERON:0001120	50.88	gold quality
endocervix	UBERON:0000458	50.49	gold quality
ectocervix	UBERON:0012249	50.29	gold quality
prefrontal cortex	UBERON:0000451	50.27	gold quality
colonic epithelium	UBERON:0000397	49.66	gold quality
left uterine tube	UBERON:0001303	48.02	gold quality
myometrium	UBERON:0001296	46.62	gold quality
smooth muscle tissue	UBERON:0001135	45.88	gold quality
fallopian tube	UBERON:0003889	45.46	gold quality
superior frontal gyrus	UBERON:0002661	45.38	silver quality
primary visual cortex	UBERON:0002436	43.27	gold quality
ventricular zone	UBERON:0003053	43.21	gold quality
frontal cortex	UBERON:0001870	42.78	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	42.09	gold quality
bone marrow cell	CL:0002092	42.03	gold quality
substantia nigra	UBERON:0002038	40.63	gold quality
sural nerve	UBERON:0015488	40.47	gold quality
brain	UBERON:0000955	39.16	gold quality
cerebral cortex	UBERON:0000956	38.73	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-79	yes	402.07
E-GEOD-109979	no	114.69
E-ANND-3	no	0.50

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 29)

• Insulin receptor substrate 4 associates with the protein IRAS (PMID:11912194)
• IRS-4 does not function as a substrate of the insulin and the IGF-I receptor in primary muscle cells but may be involved in nonreceptor tyrosine kinase signaling. (PMID:12639902)
• data demonstrate cell-specific alterations in IRS protein concentrations in theca cells from polycystic ovaries consistent with exaggerated amplification of the insulin signal & which may play a role in ovarian hyperandrogenism & thecal hyperplasia (PMID:15155816)
• insulin receptor substrate-4 and ShcA have roles in signaling by the fibroblast growth factor receptor (PMID:15316024)
• IRS-4 is subject to regulation by TNF-alpha, and PP4 mediates TNF-alpha-induced degradation of IRS-4 (PMID:15331607)
• endogenous Brk and IRS-4 interact in A431 human epidermoid carcinoma cells (PMID:15870689)
• IRS-4 plays an important role in HepG2 proliferation/differentiation and exerts its actions through ERK and p70S6K activation in a ras/raf/MEK1/2- and PI3Kinase/Akt-independent manner and in a PKC-dependent way (PMID:17408801)
• Transgenic rat gene WDR6 interacts with insulin receptor substrate 4 (IRS-4) in the rat brain and may participate in signaling and regulation of feeding behavior and longevity in the brain. (PMID:17720279)
• 53BP2S interacts and modulates the insulin signals mediated by insulin receptor substrates. (PMID:17965023)
• Data demonstrate that IRS4 interacts with the LR. This recruitment is leptin dependent and requires phosphorylation of the Y1077 motif of the LR. (PMID:18165436)
• The association and altered regulation of IRS proteins by Ad5E1A contribute to the adenovirus-transformed phenotype and modulates viral infection in an Akt-dependent manner. (PMID:19029952)
• The t(X;6) in subungual exostosis results in transcriptional deregulation of the gene for insulin receptor substrate 4. (PMID:20340132)
• IRS-4 gene is not of importance for aetiology of the vast majority of schizophrenia cases, but a single patient with schizophrenia and a mutation in IRS-4 points to that the insulin signalling system is of interest in the search for schizophrenia genes (PMID:21407155)
• Study for the first time identified IRS4 mutations in T-ALL. (PMID:21517825)
• We genotyped single-nucleotide polymorphisms of IGF1, IGF2, IGF1R, IGF2R, IGFBP1, IGFBP3, IGFBP5, IRS1, IRS2, and IRS in pancreatic cancer patients (PMID:21852217)
• This study clearly demonstrates associations between body mass index and IRS-4 variants in schizophrenia patients, but not in healthy controls, pointing to a possible involvement of IRS-4 in the control of body weight in schizophrenia. (PMID:22167131)
• Overexpression of IRS4 in U2OS cells activates PI3K signalling. (PMID:24039912)
• The association of IRS4 with SSH1 contributes to localized activation of cofilin in membrane protrusions. (PMID:25100728)
• IRS4 overexpression is associated with cancer. (PMID:27869826)
• these results demonstrated that miR-493 acts as a tumor suppressor and inhibits cell proliferation and cell cycle in human melanoma by directly targeting IRS4. (PMID:28475006)
• increase of IRS-4 expression may be involved to some extent in colorectal cancer. (PMID:29185229)
• IRS4, as a new substrate of CHIP, is negatively regulated by CK1gamma2 at the posttranslational level. (PMID:30026872)
• Mutations in IRS4 are associated with isolated congenital central hypothyroidism (CeH) in male carriers. As IRS4 is involved in leptin signalling, the phenotype may be related to disrupted leptin signalling. (PMID:30061370)
• IRS4 promotes the progression of non-small cell lung cancer and confers resistance to EGFR-TKI through the activation of PI3K/Akt and Ras-MAPK pathways. (PMID:33894221)
• Screening for Mutations in Isolated Central Hypothyroidism Reveals a Novel Mutation in Insulin Receptor Substrate 4. (PMID:34093435)
• Chronic venous disease patients show increased IRS-4 expression in the great saphenous vein wall. (PMID:34590920)
• FER-mediated phosphorylation and PIK3R2 recruitment on IRS4 promotes AKT activation and tumorigenesis in ovarian cancer cells. (PMID:35550247)
• Patients with Invasive Lobular Carcinoma Show a Significant Increase in IRS-4 Expression Compared to Infiltrative Ductal Carcinoma-A Histopathological Study. (PMID:35743985)
• Further Delineation of Central Congenital Hypothyroidism due to Variants in TBL1X and IRS4. (PMID:36860195)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	irs4a	ENSDARG00000086551
mus_musculus	Irs4	ENSMUSG00000054667
rattus_norvegicus	AABR07040887.1	ENSRNOG00000046790
drosophila_melanogaster	chico	FBGN0024248

Paralogs (2): IRS1 (ENSG00000169047), IRS2 (ENSG00000185950)

Protein

Protein identifiers

Insulin receptor substrate 4 — O14654 (reviewed: O14654)

Alternative names: 160 kDa phosphotyrosine protein, Phosphoprotein of 160 kDa

All UniProt accessions (2): A0A804CF45, O14654

UniProt curated annotations — full annotation on UniProt →

Function. Acts as an interface between multiple growth factor receptors possessing tyrosine kinase activity, such as insulin receptor, IGF1R and FGFR1, and a complex network of intracellular signaling molecules containing SH2 domains. Involved in the IGF1R mitogenic signaling pathway. Promotes the AKT1 signaling pathway and BAD phosphorylation during insulin stimulation without activation of RPS6KB1 or the inhibition of apoptosis. Interaction with GRB2 enhances insulin-stimulated mitogen-activated protein kinase activity. May be involved in nonreceptor tyrosine kinase signaling in myoblasts. Plays a pivotal role in the proliferation/differentiation of hepatoblastoma cell through EPHB2 activation upon IGF1 stimulation. May play a role in the signal transduction in response to insulin and to a lesser extent in response to IL4 and GH on mitogenesis. Plays a role in growth, reproduction and glucose homeostasis. May act as negative regulators of the IGF1 signaling pathway by suppressing the function of IRS1 and IRS2.

Subunit / interactions. Interacts with SOCS6 in response to stimulation with either insulin or IGF1. Interacts with CRK and CRKL. Interaction with CRK is stronger than with CRKL. Interacts with CRK via the phosphorylated YXXM motifs. Interacts with GRB2 and PIK3R1. Interacts with PLC-gamma, SHC1, PTK6, PPP4C and NISCH. Interacts with ASB4; this interaction promotes IRS4 proteasomal degradation.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in myoblasts. Expressed in liver and hepatocellular carcinoma.

Post-translational modifications. Phosphorylated on tyrosine residues in response to both insulin and IGF1 signaling. Phosphorylated on Tyr-921 in response to FGF2 signaling. Phosphorylation of Tyr-921 is required for GRB2, phospholipase C-gamma and phosphatidylinositol 3-kinase interaction. Ubiquitinated in a ASB4-dependent manner, leading to proteasomal degradation.

Disease relevance. Hypothyroidism, congenital, non-goitrous, 9 (CHNG9) [MIM:301035] A form of central hypothyroidism, a disorder characterized by sub-optimal thyroid hormone secretion, due to insufficient stimulation by thyrotropin of an otherwise normal thyroid gland. It may be caused by congenital or acquired disorders of the pituitary gland or hypothalamus. CHNG9 is a congenital, X-linked recessive form. Patients have a small thyroid gland with low free T4 levels and inappropriately normal levels of thyrotropin. The disease is caused by variants affecting the gene represented in this entry.

Induction. Down-regulated by PPP4C in a phosphatase activity-dependent manner.

RefSeq proteins (2): NP_001366079, NP_003595 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001849	PH_domain	Domain
IPR002404	IRS_PTB	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR039011	IRS	Family

Pfam: PF02174

UniProt features (41 total): compositionally biased region 13, sequence variant 8, short sequence motif 7, region of interest 5, mutagenesis site 4, domain 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14654-F1	49.06	0.11

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): 921

Mutagenesis-validated functional residues (4):

Position	Phenotype
700	no effect. reduces interaction with crk by 50%; when associated with f-717. abolishes interaction with crk; when associa
717	no effect. reduces interaction with crk by 50%; when associated with f-700. abolishes interaction with crk; when associa
743	no effect. reduces interaction with crk by 50%; when associated with f-779. abolishes interaction with crk; when associa
779	no effect. reduces interaction with crk by 50%; when associated with f-743. abolishes interaction with crk; when associa

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-2428928	IRS-related events triggered by IGF1R
R-HSA-162582	Signal Transduction
R-HSA-2404192	Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)
R-HSA-2428924	IGF1R signaling cascade
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 124 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, RNGTGGGC_UNKNOWN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, FREAC2_01, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, FOXO4_01, FOXO1_01, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, FOXD3_01, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_RESPONSE_TO_INSULIN, NF1_Q6_01, USF_01, HFH8_01

GO Biological Process (2): signal transduction (GO:0007165), insulin receptor signaling pathway (GO:0008286)

GO Molecular Function (3): insulin receptor binding (GO:0005158), phosphatidylinositol 3-kinase binding (GO:0043548), protein binding (GO:0005515)

GO Cellular Component (3): cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
IGF1R signaling cascade	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
signaling receptor binding	1
protein binding	1
binding	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1550 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IRS4	GRB2	P29354	917
IRS4	IRS2	Q9Y4H2	845
IRS4	INSR	P06213	747
IRS4	CRK	P46108	727
IRS4	IRS1	P35568	718
IRS4	TLE7	A0A1W2PR48	716
IRS4	SOCS7	O14512	713
IRS4	SOCS4	Q8WXH5	709
IRS4	DOK5	Q9P104	661
IRS4	DOK4	Q8TEW6	621
IRS4	ASB4	Q9Y574	600
IRS4	PTPN11	Q06124	584
IRS4	INS	P01308	565
IRS4	SOCS6	O14544	558
IRS4	C12orf75	Q8TAD7	555

IntAct

209 interactions, top by confidence:

A	B	Type	Score
PIK3R1	PIK3CD	psi-mi:“MI:0914”(association)	0.890
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
PIK3R3	PIK3CD	psi-mi:“MI:0914”(association)	0.800
NS	PIK3R2	psi-mi:“MI:0914”(association)	0.750
OPG044	DDX3X	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PKN3	ARHGAP10	psi-mi:“MI:0914”(association)	0.680
IRS4	YWHAE	psi-mi:“MI:0915”(physical association)	0.650
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
PIK3R2	IRS4	psi-mi:“MI:0914”(association)	0.640
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
MAP1LC3A	IRS4	psi-mi:“MI:0407”(direct interaction)	0.590
PPP5C	IRS4	psi-mi:“MI:0914”(association)	0.570
PPP5C	IRS4	psi-mi:“MI:2364”(proximity)	0.570
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAZ	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
NS	PIK3R2	psi-mi:“MI:0914”(association)	0.560
MTNR1A	PGRMC1	psi-mi:“MI:0914”(association)	0.530
MTNR1B	IRS4	psi-mi:“MI:0914”(association)	0.530

BioGRID (439): IRS4 (Affinity Capture-MS), IRS4 (Proximity Label-MS), IRS4 (Proximity Label-MS), IRS4 (Proximity Label-MS), IRS4 (Proximity Label-MS), IRS4 (Affinity Capture-MS), IRS4 (Affinity Capture-MS), IRS4 (Affinity Capture-MS), IRS4 (Affinity Capture-MS), IRS4 (Affinity Capture-MS), IRS4 (Affinity Capture-MS), IRS4 (Affinity Capture-MS), IRS4 (Affinity Capture-MS), IRS4 (Reconstituted Complex), IRS4 (Reconstituted Complex)

ESM2 similar proteins: A5PKW4, A7M7C7, A7X8B9, A7X8C2, A7X8C4, A7X8C9, A7X8D4, A7XW16, B1AZP2, D6RIA3, E9Q9W7, F1MUS9, O14512, O14654, O43182, O60292, O95886, P84550, P84551, P91620, P97838, P97839, P98081, Q00587, Q15464, Q17QW1, Q18PD9, Q3UHD9, Q5DTT2, Q5RBI7, Q5VZ18, Q69Z36, Q69ZH9, Q6NR09, Q6PD21, Q6PFD5, Q6T4R5, Q7L2J0, Q8BSD5, Q8BX46

Diamond homologs: B3MPN6, B3N946, B4HWI2, B4NZ70, O14654, P35568, P35569, P35570, P81122, P84770, Q28224, Q5RJW5, Q6P4Y6, Q91615, Q9DF49, Q9XTN2, Q9Y4H2, Q9Z0Y7

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
CSNK1G2	“down-regulates quantity by destabilization”	IRS4	phosphorylation
STUB1	“down-regulates quantity by destabilization”	IRS4	polyubiquitination
IRS4	“up-regulates activity”	SSH1	binding
IGF1R	up-regulates	IRS4	phosphorylation
INSR	“up-regulates activity”	IRS4	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 175 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
Signaling by ERBB2 ECD mutants	8	42.3×	3e-09
Activation of BAD and translocation to mitochondria	7	42.0×	1e-08
Constitutive Signaling by EGFRvIII	7	39.3×	2e-08
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	37.0×	3e-08
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	37.0×	3e-08
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	8	32.7×	1e-08
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	7	31.5×	8e-08
Activation of BH3-only proteins	8	31.3×	1e-08

GO biological processes:

GO term	Partners	Fold	FDR
phosphatidylinositol 3-kinase/protein kinase B signal transduction	10	13.9×	3e-06
protein targeting	5	12.1×	6e-03
intrinsic apoptotic signaling pathway	5	11.9×	6e-03
positive regulation of cell growth	8	9.7×	5e-04
Ras protein signal transduction	7	9.5×	2e-03
insulin receptor signaling pathway	6	8.8×	6e-03
MAPK cascade	8	8.1×	2e-03
G1/S transition of mitotic cell cycle	6	8.0×	9e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — BLCA, PAAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	133
Likely benign	19
Benign	9

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
691494	NM_001379150.1(IRS4):c.3161_3165del (p.Cys1054fs)	Pathogenic
1678454	NM_001379150.1(IRS4):c.3052G>T (p.Glu1018Ter)	Likely pathogenic
691492	NM_001379150.1(IRS4):c.643G>T (p.Gly215Ter)	Likely pathogenic

SpliceAI

530 predictions. Top by Δscore:

Variant	Effect	Δscore
X:108732578:CCT:C	donor_gain	1.0000
X:108722520:CACT:C	acceptor_gain	0.9900
X:108722522:CT:C	acceptor_gain	0.9900
X:108722519:TCACT:T	acceptor_gain	0.9800
X:108722520:CACTC:C	acceptor_gain	0.9800
X:108722524:C:CC	acceptor_gain	0.9800
X:108732574:CCGA:C	donor_gain	0.9800
X:108732577:A:AC	donor_gain	0.9800
X:108732578:C:CC	donor_gain	0.9800
X:108732580:T:TA	donor_gain	0.9800
X:108732604:A:AC	donor_gain	0.9800
X:108734903:T:TA	donor_gain	0.9700
X:108732625:T:A	donor_gain	0.9600
X:108732631:G:C	donor_gain	0.9600
X:108734899:T:TA	donor_gain	0.9600
X:108732629:A:AC	donor_gain	0.9500
X:108732630:C:CC	donor_gain	0.9500
X:108722521:ACTC:A	acceptor_loss	0.9300
X:108722523:TC:T	acceptor_loss	0.9300
X:108722524:CTAGG:C	acceptor_loss	0.9300
X:108722525:T:G	acceptor_loss	0.9300
X:108722535:A:C	acceptor_loss	0.9300
X:108732570:A:AC	donor_gain	0.9300
X:108732575:CGACC:C	donor_gain	0.9300
X:108732576:GAC:G	donor_gain	0.9300
X:108732577:ACCTC:A	donor_gain	0.9300
X:108722538:A:AC	acceptor_loss	0.9200
X:108732578:C:G	donor_gain	0.9200
X:108732623:ATT:A	donor_gain	0.9200
X:108732579:C:G	donor_gain	0.9100

AlphaMissense

8122 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:108735395:G:T	A317D	0.999
X:108735419:A:C	M309R	0.999
X:108735423:A:G	W308R	0.999
X:108735423:A:T	W308R	0.999
X:108735425:A:G	L307P	0.999
X:108735466:G:C	F293L	0.999
X:108735466:G:T	F293L	0.999
X:108735468:A:G	F293L	0.999
X:108735469:G:C	F292L	0.999
X:108735469:G:T	F292L	0.999
X:108735470:A:G	F292S	0.999
X:108735471:A:G	F292L	0.999
X:108735500:A:T	I282N	0.999
X:108735578:A:G	L256P	0.999
X:108735629:A:T	V239D	0.999
X:108735642:A:G	W235R	0.999
X:108735642:A:T	W235R	0.999
X:108735777:A:G	W190R	0.999
X:108735777:A:T	W190R	0.999
X:108735991:G:C	F118L	0.999
X:108735991:G:T	F118L	0.999
X:108735992:A:G	F118S	0.999
X:108735993:A:G	F118L	0.999
X:108736057:G:C	F96L	0.999
X:108736057:G:T	F96L	0.999
X:108736058:A:G	F96S	0.999
X:108736059:A:G	F96L	0.999
X:108736084:T:A	K87N	0.999
X:108736084:T:G	K87N	0.999
X:108735419:A:T	M309K	0.998

dbSNP variants (sampled 300 via entrez): RS1000393283 (X:108729032 G>A), RS1000470582 (X:108729629 T>C), RS1000500463 (X:108737416 G>A), RS1000675999 (X:108728646 T>C), RS1001132363 (X:108728155 C>G), RS1001331596 (X:108736759 G>A,T), RS1001446060 (X:108737017 C>T), RS1001846756 (X:108729170 A>G), RS1001852255 (X:108738479 T>C), RS1002332287 (X:108738474 G>A,C), RS1002741600 (X:108721785 T>C), RS1002969438 (X:108731881 G>A), RS1003600321 (X:108736491 A>G), RS1003779837 (X:108724835 T>G), RS1004155033 (X:108724494 C>T)

Disease associations

OMIM: gene MIM:300904 | disease phenotypes: MIM:301035

GenCC curated gene-disease

Disease	Classification	Inheritance
hypothyroidism, congenital, nongoitrous, 9	Strong	X-linked

Mondo (1): hypothyroidism, congenital, nongoitrous, 9 (MONDO:0026732)

Orphanet (0):

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0001419	X-linked recessive inheritance
HP:0003623	Neonatal onset
HP:0004322	Short stature
HP:0005990	Thyroid hypoplasia
HP:0011787	Central hypothyroidism
HP:0033075	Inappropriately normal thyroid-stimulating hormone level
HP:0033078	Decreased circulating free T4 concentration

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	2
trichostatin A	decreases expression	1
ferrous chloride	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Grape Seed Proanthocyanidins	increases expression, affects cotreatment	1
Arsenates	affects cotreatment, increases expression	1
Atrazine	affects cotreatment, increases expression	1
Catechin	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases expression	1

Clinical trials (associated diseases)

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