SOX3

Summary

SOX3 (SRY-box transcription factor 3, HGNC:11199) is a protein-coding gene on chromosome Xq27.1, encoding Transcription factor SOX-3 (P41225). Transcription factor required during the formation of the hypothalamo-pituitary axis.

This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins. Mutations in this gene have been associated with X-linked cognitive disability with growth hormone deficiency.

Source: NCBI Gene 6658 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability, X-linked, with panhypopituitarism (Definitive, GenCC) — +9 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 115 total — 5 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 71
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity emerging evidence
• MANE Select transcript: NM_005634

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11199
Approved symbol	SOX3
Name	SRY-box transcription factor 3
Location	Xq27.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000134595
Ensembl biotype	protein_coding
OMIM	313430
Entrez	6658

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000370536

RefSeq mRNA: 1 — MANE Select: NM_005634 NM_005634

CCDS: CCDS14669

Canonical transcript exons

ENST00000370536 — 1 exons

Exon	Start	End
ENSE00001452966	140502985	140505069

Expression profiles

Bgee: expression breadth broad, 72 present calls, max score 95.58.

FANTOM5 (CAGE): breadth broad, TPM avg 9.3465 / max 453.6958, expressed in 362 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200729	6.7027	236
200726	1.2122	111
200725	1.0639	114
209834	0.3438	111
200727	0.0239	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	95.58	gold quality
ganglionic eminence	UBERON:0004023	86.41	gold quality
embryo	UBERON:0000922	85.82	gold quality
right uterine tube	UBERON:0001302	84.50	gold quality
secondary oocyte	CL:0000655	71.12	silver quality
oviduct epithelium	UBERON:0004804	67.74	silver quality
fallopian tube	UBERON:0003889	66.33	gold quality
hypothalamus	UBERON:0001898	62.30	gold quality
amygdala	UBERON:0001876	58.64	gold quality
adenohypophysis	UBERON:0002196	58.19	gold quality
pituitary gland	UBERON:0000007	58.12	gold quality
cortical plate	UBERON:0005343	57.73	gold quality
nucleus accumbens	UBERON:0001882	57.36	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	57.08	gold quality
spinal cord	UBERON:0002240	55.59	gold quality
endothelial cell	CL:0000115	55.54	gold quality
anterior cingulate cortex	UBERON:0009835	55.07	gold quality
cingulate cortex	UBERON:0003027	55.04	gold quality
temporal lobe	UBERON:0001871	54.55	gold quality
substantia nigra	UBERON:0002038	54.32	gold quality
right testis	UBERON:0004534	54.25	gold quality
ileal mucosa	UBERON:0000331	54.07	silver quality
Ammon’s horn	UBERON:0001954	53.19	gold quality
forebrain	UBERON:0001890	53.18	gold quality
prefrontal cortex	UBERON:0000451	53.11	gold quality
midbrain	UBERON:0001891	52.81	gold quality
medial globus pallidus	UBERON:0002477	52.64	gold quality
heart right ventricle	UBERON:0002080	52.62	gold quality
left testis	UBERON:0004533	52.51	gold quality
cranial nerve II	UBERON:0000941	52.47	silver quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	55.99
E-MTAB-10485	no	367.21
E-MTAB-6142	no	19.46
E-ANND-3	no	0.46

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

7 targets.

Target	Regulation
CYP19A1	Activation
FGF3	Repression
FGF8	Repression
GMNN	Activation
LMX1B	Repression
POU5F1	Repression
SOX2	Activation

Upstream regulators (CollecTRI, top): CHD8, LEF1, MEIS1, NFYA, NFYB, NFYC, PBX1, PDX1, SOX2, SP1, TGIF1, USF1

miRNA regulators (miRDB)

39 targeting SOX3, 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-3163	100.00	77.23	8605
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-548AS-3P	99.12	69.12	2294
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-194-5P	99.01	69.65	1465
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-4520-3P	98.75	66.55	963
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-624-3P	98.37	67.06	1067
HSA-MIR-6732-3P	98.17	67.52	802
HSA-MIR-510-5P	97.66	65.82	916
HSA-MIR-6849-3P	97.25	64.57	1371

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 2 (emerging evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deficiency (PMID:12428212)
• “… mechanisms underlying X-linked hypopituitarism are…being unravelled, with involvement of SOX3 in a pedigree with X-linked mental retardation …isol. growth hormone defic., and PHF6 in two siblings with Borjeson-F-Leahmann syndrome.” p. 1208 (PMID:14714741)
• Three nucleotide substitutions (609 T–>C, 732 A–>C, and 978 G–>A) were identified, none of which altered the amino acid sequence, suggesting that they are polymorphic variants. (PMID:15292361)
• Interestingly, all X linked hypopituitarism duplications contain SOX3 (PMID:15342697)
• SUMO-1 represses transcriptional activity of SOX3. (PMID:15788563)
• We conclude that both over- and underdosage of SOX3 are associated with similar phenotypes, consisting of infundibular hypoplasia and hypopituitarism but not necessarily MR. (PMID:15800844)
• liganded RXRalpha is a potent activator of endogenous SOX3 protein expression (PMID:17005281)
• Deregulation of SOX3 target genes may contribute to dysfunction of the hypothalamic-pituitary axis in X-linked Hypopituitarism patients. (PMID:17127446)
• have implicated duplications of SOX3 and mutations of both SOX2 and SOX3 in the aetiology of variants of septo-optic dysplasia (PMID:17587179)
• Mutation by deletion of a polyalanine tract does not segregate with mental retardation. (PMID:17627381)
• Our data indicate that multiple CCAAT control elements are involved in the regulation of the SOX3 promoter, suggesting that NF-Y functions as a key regulator of SOX3 gene expression. (PMID:17910945)
• of the Xq27.1 breakpoint localized it to a 90 kb interval 3’ of the SOX3 gene, supporting a novel role of SOX3 misexpression in the development of Peters anomaly of the eye (PMID:17994562)
• Data demonstrated that overexpressed PBX1 and MEIS1 increased endogenous SOX3 protein expression in both uninduced and RA-induced NT2/D1 cells. (PMID:19799567)
• SRY is a hybrid of DGCR8 and SOX3, and is regulated by the transcription factor CP2. (PMID:19902333)
• identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal (PMID:21183788)
• these results strongly support the pathogenicity of the identified insertions near SOX3 and establish X-linked congenital hypertrichosis syndrome as a genomic disorder. (PMID:21636067)
• TGIF (TG-interacting factor) is an additional TALE superfamily member involved in the regulation of human SOX3 gene expression (PMID:22293114)
• Data indicate that HESX1, LHX4 and SOX3 polymorphisms may be associated with pituitary stalk interruption syndrome (PSIS). (PMID:23199197)
• Results indicate positive expression of SOX2, SOX3, PAX6, OCT3/4, and NANOG in the CD105+ and CD105(-) cell subpopulations. (PMID:23211052)
• Overexpression of Sox3 is associated with esophageal squamous cell carcinoma. (PMID:23238694)
• the results point at CREB as a positive regulator of SOX3 gene transcription in NT2/D1 cells, while its contribution to RA induction of SOX3 promoter is not prominent. (PMID:24257117)
• Our study provides additional evidence that deletion in polyalanine tracts of SOX3 is associated with hypopituitarism (PMID:24346842)
• SOX3 duplication is a genetic cause for XH but has incomplete penetrance. Moreover, increased SOX3 levels may be a risk factor for NTD and potentially other clinical characteristics. (PMID:24737742)
• Screening for SOX3 should be advised not only for hypopituitary patients with an ectopic posterior pituitary, but also for those with a structurally normal pituitary (PMID:25140394)
• Translocations interrupting this region may also affect the gonadal development, possibly depending on the chromatin context of the recipient chromosome. SOX3 duplications may substitute SRY in some XX subjects (PMID:25351776)
• SOX3 overdosage permits normal sex development in 46,XX individuals with random X inactivation. (PMID:25791725)
• Marked phenotypic variable expression among brothers with duplication of Xq27.1 involving the SOX3 gene. (PMID:26352083)
• Data indicate that SRY-box 3 transcription factor SOX-3 targets Src kinase in epithelial ovarian cancer (EOC) cells. (PMID:27251670)
• deletion of the SOX3 gene may have a role in intellectual disability with hemophilia B (PMID:27477789)
• Results show that SOX3 is upregulated in human osteosarcoma (OS) tissues and provide evidence that SOX3 promotes migration, invasiveness, and EMT in OS cells via transcriptional activation of Snail1 expression. (PMID:28335789)
• These findings demonstrate the novel mechanism by which Sox3 contributes to endometrial cancer stem cell invasion and suggest that repression of Sox3 by microRNA-194 may have therapeutic potential to suppress endometrial carcinoma metastasis. The cancer stem cell marker, CD133, might be the surface marker of endometrial cancer stem cell. (PMID:28618953)
• we provide a first map of the epigenetic landscape of SOX3 in pluripotent cells and during the early phases of neural differentiation. We found SOX3 gene to be non methylated from undifferentiated NT2/D1 to cells committed towards neural lineage. (PMID:28886103)
• Pathogenic missense mutation in SOX3 gene is associated with intellectual disability, microphthalmia, coloboma, hypopituitarism, facial dysmorphology and dental anomalies, including microcephaly, retrognathia and a solitary median maxillary central incisor amongst other features. (PMID:29175558)
• our data indicate that SOX3 may serve as an oncogene in osteosarcoma (PMID:29484385)
• This is the first study to report that the rare SOX3 missense variant associated with hypopituitarism possibly due to increased activation of SOX3 target genes and disregulation of beta-catenin target genes. (PMID:30125608)
• SOX3 can promote the malignant behavior of glioblastoma cells. (PMID:30209685)
• MiR-483 suppresses cell proliferation and promotes cell apoptosis by targeting SOX3 in breast cancer. (PMID:30915751)
• SOX3 duplication is a genomic imbalance involved in the pathogenesis of neural tube defects. (PMID:31299102)
• This is the largest series reported to date of unrelated patients with congenital hypopituitarism in association with Xq27.1 duplication encompassing SOX3. (PMID:31678974)
• Serum proteome profiling reveals SOX3 as a candidate prognostic marker for gastric cancer. (PMID:32363730)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	sox3	ENSDARG00000053569
mus_musculus	Sox3	ENSMUSG00000045179
rattus_norvegicus	Sox3	ENSRNOG00000058173
drosophila_melanogaster	Sox14	FBGN0005612
drosophila_melanogaster	Sox21a	FBGN0036411
drosophila_melanogaster	Sox102F	FBGN0039938
caenorhabditis_elegans		WBGENE00001182
caenorhabditis_elegans		WBGENE00015716

Paralogs (20): SOX8 (ENSG00000005513), SOX30 (ENSG00000039600), SOX10 (ENSG00000100146), SOX6 (ENSG00000110693), SOX4 (ENSG00000124766), SOX21 (ENSG00000125285), SOX9 (ENSG00000125398), SOX15 (ENSG00000129194), SOX5 (ENSG00000134532), SOX13 (ENSG00000143842), SOX17 (ENSG00000164736), SOX14 (ENSG00000168875), SOX7 (ENSG00000171056), SOX11 (ENSG00000176887), SOX12 (ENSG00000177732), CFAP65 (ENSG00000181378), SOX2 (ENSG00000181449), SOX1 (ENSG00000182968), SRY (ENSG00000184895), SOX18 (ENSG00000203883)

Protein

Protein identifiers

Transcription factor SOX-3 — P41225 (reviewed: P41225)

All UniProt accessions (1): P41225

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor required during the formation of the hypothalamo-pituitary axis. May function as a switch in neuronal development. Keeps neural cells undifferentiated by counteracting the activity of proneural proteins and suppresses neuronal differentiation. Required also within the pharyngeal epithelia for craniofacial morphogenesis. Controls a genetic switch in male development. Is necessary for initiating male sex determination by directing the development of supporting cell precursors (pre-Sertoli cells) as Sertoli rather than granulosa cells.

Subunit / interactions. Interacts with SOX2 and FGFR1.

Subcellular location. Nucleus.

Disease relevance. Panhypopituitarism X-linked (PHPX) [MIM:312000] Affected individuals have absent infundibulum, anterior pituitary hypoplasia, and ectopic posterior pituitary. The disease is caused by variants affecting the gene represented in this entry. Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency (MRXGH) [MIM:300123] A disorder characterized by the association of variable degrees of intellectual disability with panhypopituitarism, variable combinations of hypothyroidism, delayed pubertal development, and short stature due to growth hormone deficiency. The disease is caused by variants affecting the gene represented in this entry. 46,XX sex reversal 3 (SRXX3) [MIM:300833] A condition in which male gonads develop in a genetic female (female to male sex reversal). The disease is caused by variants affecting the gene represented in this entry. Copy number variations (CNV) encompassing or in close proximity to SOX3 are responsible for XX male reversal. These variations include two duplications of approximately 123 kb and 85 kb, the former of which spans the entire SOX3 gene; a 343 kb deletion immediately upstream of SOX3 that is probably responsible of altered regulation (and not increased dosage) of SOX3; a large (approximately 6 Mb) duplication that encompasses SOX3 and at least 18 additional distally located genes. Its proximal breakpoint falls within the SOX3 regulatory region. This large rearrangement has been found in a patient with XX male reversal and a complex phenotype that also includes a scrotal hypoplasia, microcephaly, developmental delay, and growth retardation. Hypoparathyroidism, X-linked (HYPX) [MIM:307700] An X-linked form of true hypoparathyroidism characterized by neonatal or infantile onset and absence of parathyroid glands. Clinical features are hypocalcemia, hyperphosphatemia, seizures, tetany and cramps. The gene represented in this entry may be involved in disease pathogenesis. A disease causing, complex chromosomal rearrangement [del(X)(q27.1)inv ins(X;2)(q27.1;p25.3)] has been found in a family with X-linked hypoparathyroidism. This chromosomal abnormality is located 67 kb downstream of SOX3 and likely results in altered SOX3 expression with pathological consequences.

Domain organisation. The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.

RefSeq proteins (1): NP_005625* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009071	HMG_box_dom	Domain
IPR022097	SOX_fam	Family
IPR036910	HMG_box_dom_sf	Homologous_superfamily
IPR050140	SRY-related_HMG-box_TF-like	Family

Pfam: PF00505, PF12336

UniProt features (14 total): sequence conflict 4, sequence variant 3, region of interest 2, compositionally biased region 2, chain 1, DNA-binding region 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41225-F1	58.40	0.20

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-3769402	Deactivation of the beta-catenin transactivating complex
R-HSA-162582	Signal Transduction
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT

MSigDB gene sets: 267 (showing top): CREL_01, LEE_NEURAL_CREST_STEM_CELL_DN, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOZGIT_ESR1_TARGETS_DN, GOBP_SEX_DETERMINATION, GOBP_PITUITARY_GLAND_DEVELOPMENT, GOBP_NEUROGENESIS, GOBP_FOREBRAIN_DEVELOPMENT, ATGTTAA_MIR302C, GOBP_HYPOTHALAMUS_DEVELOPMENT, NFKB_C, DAWSON_METHYLATED_IN_LYMPHOMA_TCL1, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_REGULATION_OF_NEURON_DIFFERENTIATION, BRN2_01

GO Biological Process (12): negative regulation of transcription by RNA polymerase II (GO:0000122), central nervous system development (GO:0007417), brain development (GO:0007420), sensory organ development (GO:0007423), sex determination (GO:0007530), hypothalamus development (GO:0021854), pituitary gland development (GO:0021983), neuron differentiation (GO:0030182), negative regulation of neuron differentiation (GO:0045665), positive regulation of transcription by RNA polymerase II (GO:0045944), face development (GO:0060324), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (6): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	1
Signal Transduction	1
Signaling by WNT	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
animal organ development	2
head development	2
diencephalon development	2
anatomical structure development	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
nervous system development	1
system development	1
central nervous system development	1
developmental process involved in reproduction	1
limbic system development	1
endocrine system development	1
gland development	1
cell differentiation	1
generation of neurons	1
neuron differentiation	1
negative regulation of cell differentiation	1
regulation of neuron differentiation	1
positive regulation of DNA-templated transcription	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

29 interactions, top by confidence:

A	B	Type	Score
SOX3	TRAF2	psi-mi:“MI:0915”(physical association)	0.560
SOX3	ATXN1	psi-mi:“MI:0915”(physical association)	0.560
CRX	SOX3	psi-mi:“MI:0915”(physical association)	0.560
	SOX3	psi-mi:“MI:0915”(physical association)	0.370
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
AKT1	SOX3	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	SOX3	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	SOX3	psi-mi:“MI:2364”(proximity)	0.270
SOX3	SMAD4	psi-mi:“MI:2364”(proximity)	0.270
SOX3	SMARCA4	psi-mi:“MI:2364”(proximity)	0.270
SMARCA4	SOX3	psi-mi:“MI:2364”(proximity)	0.270
SOX3	EGFR	psi-mi:“MI:2364”(proximity)	0.270
SOX3	PTEN	psi-mi:“MI:2364”(proximity)	0.270
SOX3	PTPN11	psi-mi:“MI:2364”(proximity)	0.270
SOX3	TP53	psi-mi:“MI:2364”(proximity)	0.270
ATXN1	SOX3	psi-mi:“MI:0915”(physical association)	0.000
SOX3	CRX	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): TRRAP (Affinity Capture-MS), SOX3 (Affinity Capture-MS), SOX3 (FRET), SOX3 (FRET), SOX3 (FRET), TEAD2 (FRET), SOX3 (FRET), SOX3 (FRET), AURKA (FRET), CDKN2A (FRET), MYC (FRET), NF2 (FRET), TERT (FRET), SOX3 (FRET), SOX3 (Two-hybrid)

ESM2 similar proteins: A2TED3, O00570, O57401, O95409, P06602, P07548, P09085, P14734, P16241, P20264, P22544, P23441, P23757, P31361, P32027, P32182, P32242, P35583, P39768, P40764, P41225, P43241, P43698, P43699, P48430, P48431, P48432, P50220, P53783, P53784, P54231, P54269, P56224, P80205, Q04649, Q07687, Q24255, Q24533, Q2PG84, Q2Z1R2

Diamond homologs: A2TED3, A4QNG3, B0ZTE1, B0ZTE2, O00570, O42569, O57401, O60248, O95416, P36389, P36390, P36393, P36395, P36396, P41225, P43267, P47792, P48046, P48430, P48431, P48432, P48433, P51501, P53783, P53784, P54231, P55863, P61259, Q04892, Q05066, Q20201, Q21305, Q24533, Q28447, Q28778, Q28783, Q28798, Q2PG84, Q2Z1R2, Q32PP9

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SOX3	down-regulates	CTNNB1	binding
CHD8	“down-regulates quantity”	SOX3	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	1
Uncertain significance	64
Likely benign	28
Benign	5

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
3391866	GRCh37/hg19 Xq27.1(chrX:139102161-139705958)x2	Pathogenic
4689391	NC_000023.10:g.(?139585150)(139587235_?)del	Pathogenic
9868	NM_005634.3(SOX3):c.712_744dup (p.Ala248_Ser249insAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAla)	Pathogenic
9869	SOX3, DUP	Pathogenic
9870	NM_005634.3(SOX3):c.711_731dup (p.Ala248_Ser249insAlaAlaAlaAlaAlaAlaAla)	Pathogenic
444006	NM_005634.3(SOX3):c.449C>A (p.Ser150Tyr)	Likely pathogenic

SpliceAI

16 predictions. Top by Δscore:

Variant	Effect	Δscore
X:140504399:T:C	donor_gain	0.6700
X:140503937:TTCAC:T	donor_gain	0.4200
X:140503938:TCACT:T	donor_gain	0.4200
X:140504398:AT:A	donor_gain	0.4100
X:140503941:C:CT	donor_gain	0.3500
X:140503942:T:TT	donor_gain	0.3500
X:140504398:A:AC	donor_gain	0.3400
X:140504620:C:CT	acceptor_gain	0.3100
X:140504607:C:CT	acceptor_gain	0.2700
X:140503368:AACT:A	acceptor_gain	0.2600
X:140503369:ACTA:A	acceptor_gain	0.2600
X:140504256:T:TA	acceptor_gain	0.2500
X:140503936:CTTCA:C	donor_gain	0.2300
X:140503362:A:C	acceptor_gain	0.2200
X:140503744:T:A	donor_gain	0.2000
X:140504237:ACC:A	acceptor_gain	0.2000

AlphaMissense

2850 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:140503859:A:C	I401S	1.000
X:140503859:A:G	I401T	1.000
X:140503859:A:T	I401N	1.000
X:140504424:T:C	K213E	1.000
X:140504427:G:T	R212S	1.000
X:140504430:G:T	R211S	1.000
X:140504432:G:T	P210Q	1.000
X:140504433:G:A	P210S	1.000
X:140504438:T:C	Y208C	1.000
X:140504439:A:C	Y208D	1.000
X:140504439:A:G	Y208H	1.000
X:140504440:C:A	K207N	1.000
X:140504440:C:G	K207N	1.000
X:140504441:T:A	K207M	1.000
X:140504442:T:C	K207E	1.000
X:140504444:T:C	Y206C	1.000
X:140504445:A:C	Y206D	1.000
X:140504445:A:G	Y206H	1.000
X:140504445:A:T	Y206N	1.000
X:140504462:A:G	M200T	1.000
X:140504464:G:C	H199Q	1.000
X:140504464:G:T	H199Q	1.000
X:140504465:T:C	H199R	1.000
X:140504466:G:C	H199D	1.000
X:140504466:G:T	H199N	1.000
X:140504472:C:G	A197P	1.000
X:140504474:C:G	R196P	1.000
X:140504475:G:A	R196C	1.000
X:140504475:G:T	R196S	1.000
X:140504477:A:G	L195P	1.000

dbSNP variants (sampled 300 via entrez): RS1000563870 (X:140502539 G>A,C), RS1000566639 (X:140505806 G>A), RS1001341369 (X:140503161 G>A,T), RS1002536165 (X:140504213 T>G), RS1003489142 (X:140502691 C>A,G), RS1004574326 (X:140506552 G>T), RS1006515887 (X:140506222 C>A,T), RS1006976606 (X:140502785 C>G,T), RS1007336614 (X:140503309 T>C), RS1007377802 (X:140504872 A>C,G), RS1007559909 (X:140505022 G>A), RS1007943295 (X:140505237 G>A,C), RS1010480608 (X:140502748 C>G), RS1010511876 (X:140503256 A>C), RS1011199508 (X:140506733 C>T)

Disease associations

OMIM: gene MIM:313430 | disease phenotypes: MIM:300123, MIM:312000

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, X-linked, with panhypopituitarism	Definitive	X-linked
46,XX sex reversal 3	Definitive	X-linked
panhypopituitarism, X-linked	Strong	X-linked
septooptic dysplasia	Supportive	Autosomal dominant
46,XX sex reversal 1	Supportive	Autosomal dominant
X-linked intellectual disability with isolated growth hormone deficiency	Supportive	X-linked
X-linked congenital generalized hypertrichosis	Supportive	X-linked
panhypopituitarism	Supportive	Autosomal recessive
46,XX ovotesticular disorder of sex development	Limited	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder	Moderate	XL

Mondo (11): intellectual disability, X-linked, with panhypopituitarism (MONDO:0010252), panhypopituitarism, X-linked (MONDO:0010712), intellectual disability (MONDO:0001071), premature menopause (MONDO:0001119), X-linked intellectual disability with isolated growth hormone deficiency (MONDO:0019032), 46,XX ovotesticular disorder of sex development (MONDO:0016281), septooptic dysplasia (MONDO:0008428), (MONDO:0010766), X-linked congenital generalized hypertrichosis (MONDO:0010614), panhypopituitarism (MONDO:0019591), 46,XX sex reversal 3 (MONDO:0010442)

Orphanet (2): X-linked intellectual disability with isolated growth hormone deficiency (Orphanet:67045), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

71 total (30 of 71 shown, HPO-id order):

HPO	Term
HP:0000026	Male hypogonadism
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000062	Ambiguous genitalia
HP:0000141	Amenorrhea
HP:0000147	Polycystic ovaries
HP:0000175	Cleft palate
HP:0000407	Sensorineural hearing impairment
HP:0000457	Depressed nasal ridge
HP:0000458	Anosmia
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000570	Abnormal saccadic eye movements
HP:0000609	Optic nerve hypoplasia
HP:0000639	Nystagmus
HP:0000657	Oculomotor apraxia
HP:0000717	Autism
HP:0000789	Infertility
HP:0000821	Hypothyroidism
HP:0000823	Delayed puberty
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000839	Pituitary dwarfism
HP:0000864	Abnormality of the hypothalamus-pituitary axis
HP:0000871	Panhypopituitarism
HP:0000873	Diabetes insipidus
HP:0000938	Osteopenia
HP:0000958	Dry skin
HP:0000966	Hypohidrosis
HP:0001249	Intellectual disability
HP:0001250	Seizure

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008839_417	Height	1.000000e-13

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
D050090	Ovotesticular Disorders of Sex Development	C12.050.351.875.253.343; C12.200.706.316.343; C12.800.316.343; C16.131.939.316.343; C19.391.119.343
D025962	Septo-Optic Dysplasia	C10.292.562.700.375.875; C10.500.034.937; C10.500.760.500; C11.590.436.400.875; C16.131.666.034.937; C16.131.666.763.500
C538388	Hypertrichosis congenital generalized X-linked (supp.)
C538613	Panhypopituitarism X-linked (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, decreases expression	6
trichostatin A	decreases expression, affects cotreatment	3
entinostat	decreases expression, affects cotreatment	2
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Estradiol	decreases reaction, increases expression, affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression, increases expression, increases reaction	2
bisphenol F	affects cotreatment, increases expression	1
decabromobiphenyl ether	increases expression	1
arsenite	increases methylation	1
sodium arsenite	affects methylation	1
tetrabromobisphenol A	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
tetrachlorodian	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
Temozolomide	increases expression	1
Benzo(a)pyrene	affects methylation	1
Camptothecin	increases methylation	1
Catechin	affects cotreatment, increases expression	1
Coumestrol	increases expression, affects cotreatment	1
Cytarabine	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00140413	PHASE4	COMPLETED	Endocrine Dysfunction and Growth Hormone Deficiency in Children With Optic Nerve Hypoplasia
NCT00144391	PHASE4	COMPLETED	Testosterone Gel Applied to Women With Pituitary Gland Problems
NCT00373386	PHASE4	COMPLETED	Growth Hormone and Endothelial Function in Children
NCT04897802	PHASE4	COMPLETED	Identification and Clinical Relevance of an Oxytocin Deficient State (GLP1 Study)
NCT04902235	PHASE4	COMPLETED	Identification and Clinical Relevance of an Oxytocin Deficient State (CRH Study)
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT06760546	PHASE3	RECRUITING	A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756)
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT05717855	Not specified	COMPLETED	Screening of Septo-optic Dysplasia During a Fetal Examination at 16-20 Weeks of Gestation
NCT06262152	Not specified	UNKNOWN	Sleep Profile of Patients With Septo-optic Dysplasia