SRY

Summary

SRY (sex determining region Y, HGNC:11311) is a protein-coding gene on chromosome Yp11.2, encoding Sex-determining region Y protein (Q05066). Transcriptional regulator that controls a genetic switch in male development. It is haploinsufficient (ClinGen: sufficient evidence).

This intronless gene encodes a transcription factor that is a member of the high mobility group (HMG)-box family of DNA-binding proteins. This protein is the testis-determining factor (TDF), which initiates male sex determination. Mutations in this gene give rise to XY females with gonadal dysgenesis (Swyer syndrome); translocation of part of the Y chromosome containing this gene to the X chromosome causes XX male syndrome.

Source: NCBI Gene 6736 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 46,XX sex reversal 1 (Definitive, GenCC) — +4 more curated relationships
• Clinical variants (ClinVar): 72 total — 33 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 107
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 43 downstream targets (CollecTRI)
• MANE Select transcript: NM_003140

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11311
Approved symbol	SRY
Name	sex determining region Y
Location	Yp11.2
Locus type	gene with protein product
Status	Approved
Aliases	TDF
Ensembl gene	ENSG00000184895
Ensembl biotype	protein_coding
OMIM	480000
Entrez	6736

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000383070

RefSeq mRNA: 1 — MANE Select: NM_003140 NM_003140

CCDS: CCDS14772

Canonical transcript exons

ENST00000383070 — 1 exons

Exon	Start	End
ENSE00001494622	2786855	2787682

Expression profiles

Bgee: expression breadth broad, 66 present calls, max score 87.67.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0551 / max 6.7138, expressed in 37 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
201231	0.0551	37

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.67	gold quality
tendon of biceps brachii	UBERON:0008188	63.16	silver quality
right testis	UBERON:0004534	57.96	gold quality
testis	UBERON:0000473	54.72	gold quality
left testis	UBERON:0004533	54.62	gold quality
skin of abdomen	UBERON:0001416	53.49	gold quality
tendon	UBERON:0000043	52.88	gold quality
islet of Langerhans	UBERON:0000006	52.24	gold quality
calcaneal tendon	UBERON:0003701	51.72	gold quality
skin of leg	UBERON:0001511	50.81	gold quality
zone of skin	UBERON:0000014	50.37	gold quality
ventricular zone	UBERON:0003053	50.29	gold quality
adrenal tissue	UBERON:0018303	49.93	gold quality
right adrenal gland cortex	UBERON:0035827	48.43	gold quality
right adrenal gland	UBERON:0001233	47.30	gold quality
esophagus mucosa	UBERON:0002469	44.61	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
gingival epithelium	UBERON:0001949	42.67	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
ganglionic eminence	UBERON:0004023	42.55	gold quality
vastus lateralis	UBERON:0001379	41.72	gold quality
quadriceps femoris	UBERON:0001377	41.67	gold quality
gingiva	UBERON:0001828	41.34	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
adrenal cortex	UBERON:0001235	41.23	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
ventral tegmental area	UBERON:0002691	41.01	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
amniotic fluid	UBERON:0000173	40.69	gold quality
jejunal mucosa	UBERON:0000399	40.59	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.23

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

43 targets.

Target	Regulation
ACE
ACE2
AGT	Activation
AMH
AR
CBLN4	Activation
COL4A2
CSNK1A1
CTNNB1	Activation
CYP4V2	Unknown
DAZ1	Unknown
ESR1
ETV2	Activation
FN1
FOSL1	Activation
GHRHR
HNF4A
HPGDS
HSPA1A
KLK3
MACC1
MALAT1	Repression
MAOA
MSH4	Unknown
NFAT5
NFKBIB	Unknown
NPR1
NTF3
NWD1	Activation
PROM1	Unknown

JASPAR motifs

Motif	Name	Family
MA0084.1	SRY	SOX-related factors
MA0084.2	SRY	SOX-related factors

JASPAR matrix evidence (PMIDs): PMID:8190643

Upstream regulators (CollecTRI, top): CEBPB, FOXL2, GATA4, NR5A1, SOX9, SP1, SRY, TFCP2, WT1

miRNA regulators (miRDB)

13 targeting SRY, 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-4803	99.98	71.99	3117
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-4721	99.26	66.05	818
HSA-MIR-1245B-5P	98.88	66.55	576
HSA-MIR-3142	98.88	66.09	529
HSA-MIR-1537-5P	98.70	68.33	999
HSA-MIR-4662A-5P	98.48	67.18	1007
HSA-MIR-4446-3P	97.91	64.29	991
HSA-MIR-4675	97.69	64.82	774
HSA-MIR-4741	97.69	64.14	883
HSA-MIR-101-5P	96.84	65.66	649
HSA-MIR-487B-3P	88.08	68.35	83

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• mutant SRY protein structure that modulates DNA bending (PMID:11563911)
• analyse the presence of DAZ, RBMY1, USP9Y, protamine-2, SRY and actin messenger RNA (mRNA) in testicular cells of men suffering from idiopathic azoospermia. (PMID:11869379)
• The SRY gene encodes for a protein in the high mobility group that binds to DNA in the nucleus and it regulates the transcription of other genes necessary for testis determination by acting as a repressor or activator of this process. (PMID:11912443)
• discussion of molecular action (REVIEW) (PMID:11990798)
• Familial mutation in the testis-determining gene SRY shared by an XY female and her normal father. (PMID:12107262)
• presence of hidden mosaicism for SRY or other Y sequences in some patients with XX true hermaphroditism (PMID:12215841)
• analysis of missense mutations in SRY site reveals its role in gonadal dysgenesis (PMID:12483463)
• Sry and the genetics of sex determination. Review. (PMID:12575752)
• Defective importin beta recognition and nuclear import of the sex-determining factor SRY are associated with XY sex-reversing mutations. (PMID:12764225)
• 2 new mutations of SRY were found: R72G ad Q158fX180. (PMID:12919143)
• These results suggest that WT1 forms a complex with SRY to regulate transcription and that this WT1-SRY interaction is important in testis development. (PMID:12970737)
• Results suggest the involvement of SRY gene in sex reversal which further supports the relationship between SRY alterations, gonadal dysgenesis and/or primary infertility. (PMID:15155818)
• acetylation and deacetylation of SRY may be important mechanisms for regulating SRY activity during mammalian sex determination (PMID:15297880)
• Results show that fetal SRY gene can be found at a time as early as 42 days of gestation in maternal plasma by the use of FQ-PCR. (PMID:15300641)
• We confirmed previous reports that mutations in the SRY gene are not associated with anorchia. Lack of association between genetic factors necessary for correct testicular descent and anorchia. (PMID:15579790)
• SRY nuclear import during gonadal development and disruption directly depends on calmodulin. (PMID:15746192)
• Human SRY 5’ flanking sequences supported reporter transgene expression within the genital ridge of male embryos at the time of sex determination and also supported expression within migrating truncal neural crest cells of both male and female embryos. (PMID:16411204)
• SRY tail functions as a “kinetic clamp” to regulate the lifetime of the bent DNA complex. (PMID:16504207)
• The human Y chromosome is affected by high levels of natural background radiation and can harbor copy number polymorphisms that cause sex chromosome related anomalies. (PMID:16510537)
• Male development is robust to subtle alterations in SRY-DNA architecture but depends critically on nuclear localization. (PMID:16762365)
• The AZFc variation was detected in five cases of male infertility. (PMID:17762975)
• A case of SRY(-) 46,XX monozygotic twins with genital ambiguity is reported. (PMID:18056774)
• The demonstration of SRY using FISH is useful in the assessment of gonadal specimens from patients with intersex disorders, particularly in older individuals where the diagnosis may be unsuspected clinically. (PMID:18184266)
• Critical levels of WT1 + KTS, SRY and SOX9 are required for normal Sertoli cell maturation, and subsequent normal spermatogenesis. (PMID:18271004)
• Our results suggest involvement of the SRY gene in sex reversal. (PMID:18304538)
• These findings implicate a mutation at a sex-determining locus other than SRY and SOX9 as the cause for the XX sex reversal trait in this family. (PMID:18391513)
• Here we report on the genetic investigation of an atypical XX male in which the SRY gene was located at the end of the long arm of chromosome 1. (PMID:18412126)
• The importance that full-length SRY has, particularly the C-terminal region of the protein, in DNA binding in vitro. (PMID:18453550)
• Human SRY inhibits beta catenin-mediated transcription. (PMID:18598779)
• New insights into SRY regulation through identification of 5’ conserved sequence are reported. (PMID:18851760)
• Case Report: Identification of a new mutation in the SRY gene in a 46,XY woman with Swyer syndrome. (PMID:18990383)
• Two SRY mutations and a polymorphism were identified in two patients with 46,XY complete pure gonadal dysgenesis, demonstrating the importance of the carboxy-terminal region of SRY in DNA binding activity. (PMID:19007850)
• PCR and FISH demonstrated tandem duplication/multiplication of the SRY and DAZ genes in the two Turner Syndrome patients having intact Y chromosome in >85% cells (PMID:19030103)
• a systematic search for hidden Y-chromosome mosaicism, especially SRY, in Turner syndrome patients is justified by the possibility of preventing gonadal lesions. (PMID:19188812)
• The SRY gene is key in sex determination and development, yet there might be other important genes involved. (PMID:19199262)
• Includes the study of a disease-related upstream ORF in this gene, and shows that it functions to reduce protein levels by 100%. (PMID:19372376)
• SRY represses the transcriptional of the Rspo1/Wnt target genes involved in ovarian determination. (PMID:19376480)
• mutations in a sex-determining gene (SRY) may contribute to the pathogenesis of testicular dysgenesis syndrome (TDS). (PMID:19531589)
• A markedly higher percentage of Y-containing cells was observed in the blood (68%), which was not considered to be the major reason why the case did not have distinct ambiguous genitalia. (PMID:19650415)
• The KRAB-O protein can simultaneously bind KAP1 and SRY in a noncompetitive but also noncooperative manner. (PMID:19850934)

Cross-species orthologs

20 orthologs

Organism	Symbol	Gene ID
danio_rerio	sox19a	ENSDARG00000010770
danio_rerio	sox19b	ENSDARG00000040266
danio_rerio	sox32	ENSDARG00000100591
mus_musculus	Sry	ENSMUSG00000069036
rattus_norvegicus	Sry3	ENSRNOG00000072090
rattus_norvegicus	Sry3C	ENSRNOG00000079797
rattus_norvegicus	Sry	ENSRNOG00000080005
rattus_norvegicus	Sry3A	ENSRNOG00000081394
rattus_norvegicus	Sry3b2	ENSRNOG00000082755
rattus_norvegicus	Sry2	ENSRNOG00000083264
rattus_norvegicus	Sry3B1	ENSRNOG00000083909
rattus_norvegicus	Sry4	ENSRNOG00000085288
rattus_norvegicus		ENSRNOG00000090479
drosophila_melanogaster	Sox14	FBGN0005612
drosophila_melanogaster	Sox15	FBGN0005613
drosophila_melanogaster	Sox100B	FBGN0024288
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), SOX3 (ENSG00000134595), SOX13 (ENSG00000143842), SOX17 (ENSG00000164736), SOX14 (ENSG00000168875), SOX7 (ENSG00000171056), SOX11 (ENSG00000176887), SOX12 (ENSG00000177732), CFAP65 (ENSG00000181378), SOX2 (ENSG00000181449), SOX1 (ENSG00000182968), SOX18 (ENSG00000203883)

Protein

Protein identifiers

Sex-determining region Y protein — Q05066 (reviewed: Q05066)

Alternative names: Testis-determining factor

All UniProt accessions (2): A7WPU8, Q05066

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator that controls a genetic switch in male development. It is necessary and sufficient for initiating male sex determination by directing the development of supporting cell precursors (pre-Sertoli cells) as Sertoli rather than granulosa cells. Involved in different aspects of gene regulation including promoter activation or repression. Binds to the DNA consensus sequence 5’-[AT]AACAA[AT]-3’. SRY HMG box recognizes DNA by partial intercalation in the minor groove and promotes DNA bending. Also involved in pre-mRNA splicing. In male adult brain involved in the maintenance of motor functions of dopaminergic neurons.

Subunit / interactions. Interacts with CALM, EP300, HDAC3, KPNB1, ZNF208 isoform KRAB-O, PARP1, SLC9A3R2 and WT1. The interaction with EP300 modulates its DNA-binding activity. The interaction with KPNB1 is sensitive to dissociation by Ran in the GTP-bound form. Interaction with PARP1 impaired its DNA-binding activity.

Subcellular location. Nucleus speckle. Cytoplasm. Nucleus.

Post-translational modifications. Phosphorylated on serine residues by PKA. Phosphorylation by PKA enhances its DNA-binding activity and stimulates transcription repression. Acetylation of Lys-136 contributes to its nuclear localization and enhances its interaction with KPNB1. Deacetylated by HDAC3. Poly-ADP-ribosylated by PARP1. ADP-ribosylation reduces its DNA-binding activity.

Disease relevance. 46,XY sex reversal 1 (SRXY1) [MIM:400044] A condition characterized by male-to-female sex reversal in the presence of a normal 46,XY karyotype. Patients manifest rapid and early degeneration of their gonads, which are present in the adult as ‘streak gonads’, consisting mainly of fibrous tissue and variable amounts of ovarian stroma. As a result these patients do not develop secondary sexual characteristics at puberty. The external genitalia in these subjects are completely female, and Muellerian structures are normal. The disease is caused by variants affecting the gene represented in this entry. A 45,X chromosomal aberration involving SRY is found in Turner syndrome, a disease characterized by gonadal dysgenesis with short stature, ‘streak gonads’, variable abnormalities such as webbing of the neck, cubitus valgus, cardiac defects, low posterior hair line. The phenotype is female. 46,XX sex reversal 1 (SRXX1) [MIM:400045] 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.

Domain organisation. DNA binding and bending properties of the HMG domains of human and mouse SRY differ form each other. Human SRY shows more extensive minor groove contacts with DNA and a lower specificity of sequence recognition than mouse SRY.

Similarity. Belongs to the SRY family.

RefSeq proteins (1): NP_003131* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009071	HMG_box_dom	Domain
IPR017253	SRY	Family
IPR036910	HMG_box_dom_sf	Homologous_superfamily
IPR050140	SRY-related_HMG-box_TF-like	Family

Pfam: PF00505

UniProt features (52 total): sequence variant 27, mutagenesis site 10, region of interest 7, helix 3, chain 1, DNA-binding region 1, modified residue 1, strand 1, compositionally biased region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
9BVD	X-RAY DIFFRACTION	2.48
7YHP	ELECTRON MICROSCOPY	3.1
6EDB	X-RAY DIFFRACTION	3.21
7YHO	ELECTRON MICROSCOPY	3.3
7YHQ	ELECTRON MICROSCOPY	3.9
1HRY	SOLUTION NMR
1HRZ	SOLUTION NMR
1J46	SOLUTION NMR
1J47	SOLUTION NMR
2GZK	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q05066-F1	69.01	0.40

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): 136

Mutagenesis-validated functional residues (10):

Position	Phenotype
31–33	abolishes its phosphorylation by pka. does not enhance its dna-binding activity. abolishes stimulation of transcription
62	strongly reduces nuclear localization. strongly reduces nuclear localization; when associated with w-133. reduces intera
75	strongly reduces nuclear localization. abolishes dna-binding. does not reduce interaction with kpnb1 and caml.
76	reduces nuclear localization. reduces dna-binding. does not reduce interaction with kpnb1 and caml. does not affectnucle
115	does not abolish acetylation activity.
123	does not abolish acetylation.
128	does not abolish acetylation.
133	reduces nuclear localization. strongly reduces nuclear localization; when associated with g-62. reduces interaction with
134	does not abolish acetylation.
136	abolishes acetylation. does not abolish interaction with ep300. does not abolish dna-binding. enhances cytoplasmic local

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-3769402	Deactivation of the beta-catenin transactivating complex
R-HSA-9690406	Transcriptional regulation of testis differentiation
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT

MSigDB gene sets: 318 (showing top): GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_MALE_SEX_DETERMINATION, GOBP_SEX_DETERMINATION, MODULE_59, GOBP_REPRODUCTIVE_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_REPRODUCTIVE_PROCESS, SCHLOSSER_SERUM_RESPONSE_DN, GOBP_SEX_DIFFERENTIATION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, PID_AR_TF_PATHWAY, GOBP_POSITIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS, GOBP_MALE_SEX_DIFFERENTIATION, GOBP_DEVELOPMENT_OF_PRIMARY_SEXUAL_CHARACTERISTICS, GOCC_NUCLEAR_SPECK, GOBP_POSITIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS

GO Biological Process (8): sex differentiation (GO:0007548), positive regulation of gene expression (GO:0010628), cell differentiation (GO:0030154), male sex determination (GO:0030238), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of male gonad development (GO:2000020), regulation of transcription by RNA polymerase II (GO:0006357)

GO Molecular Function (8): 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), calmodulin binding (GO:0005516), DNA-binding transcription factor binding (GO:0140297), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), nuclear speck (GO:0016607)

Reactome top-level categories

Rollup of top-4 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
developmental process involved in reproduction	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
cellular developmental process	1
multicellular organism development	1
sex determination	1
DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
male gonad development	1
positive regulation of gonad development	1
regulation of male gonad development	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
protein binding	1
transcription factor binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

2788 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SRY	ZFY	P08048	949
SRY	DMRT1	Q9Y5R6	912
SRY	NR0B1	P51843	886
SRY	WT1	P19544	876
SRY	TSPY1	P09002	863
SRY	ZFX	P17010	861
SRY	NR5A1	Q13285	858
SRY	AMH	P03971	855
SRY	RSPO1	Q2MKA7	821
SRY	WNT4	P56705	808
SRY	DMRT2	Q9Y5R5	803
SRY	FOXL2	P58012	802
SRY	UTY	O14607	750
SRY	KDM5D	Q9BY66	745
SRY	DDX3Y	O15523	730

IntAct

14 interactions, top by confidence:

A	B	Type	Score
NHERF2	SRY	psi-mi:“MI:0915”(physical association)	0.730
NHERF2	SRY	psi-mi:“MI:0407”(direct interaction)	0.730
SRY	NHERF2	psi-mi:“MI:0403”(colocalization)	0.730
SMAD3	SRY	psi-mi:“MI:0915”(physical association)	0.500
SRY	SMAD3	psi-mi:“MI:0915”(physical association)	0.500
SMAD3	PAEP	psi-mi:“MI:0914”(association)	0.350
SRY	RET	psi-mi:“MI:0914”(association)	0.350

BioGRID (33): SRY (Two-hybrid), SRY (Reconstituted Complex), UBR2 (Affinity Capture-MS), RET (Affinity Capture-MS), SRY (Reconstituted Complex), SRY (Reconstituted Complex), SRY (Reconstituted Complex), SRY (Reconstituted Complex), SRY (Affinity Capture-Western), SRY (Co-localization), SRY (Cross-Linking-MS (XL-MS)), SP1 (Co-localization), Xpo4 (Affinity Capture-Western), Xpo4 (Reconstituted Complex), EP300 (Affinity Capture-Western)

ESM2 similar proteins: P36390, P36396, P48046, P51501, Q03256, Q03257, Q05066, Q27949, Q28447, Q28778, Q28783, Q28798, Q67EX6, Q67EX7, Q6T723, Q6T724, Q6TC27, Q6TC28, Q6TC30, Q6TC31, Q6TC32, Q6TC33, Q6TC34, Q6TC36, Q6TC37, Q6TC38, Q6TC39, Q6TC40, Q6TC41, Q6TC43, Q6TC44, Q6TC45, Q6TC46, Q6TC50, Q7JGF7, Q7JGF9, Q863B7, Q863C0, Q863C2, Q864Q5

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

1 interactions.

A	Effect	B	Mechanism
WT1	up-regulates	SRY	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	11
Uncertain significance	23
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1339966	GRCh37/hg19 Yp11.31(chrY:2650140-2691749)x0	Pathogenic
2693711	NM_003140.3(SRY):c.174_175insC (p.Arg59fs)	Pathogenic
2829588	NM_003140.3(SRY):c.145G>T (p.Gly49Ter)	Pathogenic
3040170	NM_003140.3(SRY):c.294G>A (p.Trp98Ter)	Pathogenic
3242611	NC_000024.9:g.(?2654792)(2655895_?)del	Pathogenic
3338847	NM_003140.3(SRY):c.179T>C (p.Val60Ala)	Pathogenic
3652585	NM_003140.3(SRY):c.22_23del (p.Met8fs)	Pathogenic
436871	NM_003140.3(SRY):c.331C>T (p.Gln111Ter)	Pathogenic
470195	NM_003140.3(SRY):c.264dup (p.Glu89fs)	Pathogenic
470196	NM_003140.3(SRY):c.380A>G (p.Tyr127Cys)	Pathogenic
492908	NM_003140.3(SRY):c.89G>T (p.Arg30Ile)	Pathogenic
537738	NM_003140.3(SRY):c.288C>G (p.Tyr96Ter)	Pathogenic
537739	NM_003140.3(SRY):c.263C>A (p.Ser88Ter)	Pathogenic
664404	NM_003140.3(SRY):c.169C>T (p.Gln57Ter)	Pathogenic
9737	NM_003140.3(SRY):c.364_367del (p.Glu122fs)	Pathogenic
9738	NM_003140.3(SRY):c.326T>C (p.Phe109Ser)	Pathogenic
9739	NM_003140.3(SRY):c.178G>C (p.Val60Leu)	Pathogenic
9740	NM_003140.3(SRY):c.277C>T (p.Gln93Ter)	Pathogenic
9741	NM_003140.3(SRY):c.270C>G (p.Ile90Met)	Pathogenic
9742	NM_003140.3(SRY):c.317A>T (p.Lys106Ile)	Pathogenic
9743	NM_003140.3(SRY):c.324del (p.Phe109fs)	Pathogenic
9744	NM_003140.3(SRY):c.337G>A (p.Ala113Thr)	Pathogenic
9745	NM_003140.3(SRY):c.320G>A (p.Trp107Ter)	Pathogenic
9746	NM_003140.3(SRY):c.203T>C (p.Ile68Thr)	Pathogenic
9748	NM_003140.3(SRY):c.209G>A (p.Trp70Ter)	Pathogenic
9749	NM_003140.3(SRY):c.274A>T (p.Lys92Ter)	Pathogenic
9750	NM_003140.3(SRY):c.283G>C (p.Gly95Arg)	Pathogenic
9751	NM_003140.3(SRY):c.12T>A (p.Tyr4Ter)	Pathogenic
9752	NM_003140.3(SRY):c.397C>T (p.Arg133Trp)	Pathogenic
9753	NM_003140.3(SRY):c.4C>T (p.Gln2Ter)	Pathogenic

SpliceAI

172 predictions. Top by Δscore:

Variant	Effect	Δscore
Y:2787269:T:TA	donor_gain	0.7100
Y:2787137:T:TA	donor_gain	0.6800
Y:2786880:C:CT	acceptor_gain	0.6500
Y:2787066:G:C	donor_gain	0.6400
Y:2786992:CAG:C	donor_gain	0.6300
Y:2786936:T:C	donor_gain	0.6000
Y:2787108:C:A	donor_gain	0.6000
Y:2787224:T:C	donor_gain	0.5900
Y:2787223:A:AC	donor_gain	0.5700
Y:2787175:A:AC	donor_gain	0.5300
Y:2787176:C:CC	donor_gain	0.5300
Y:2786909:A:C	donor_gain	0.5000
Y:2786881:A:T	acceptor_gain	0.4900
Y:2786880:C:T	acceptor_gain	0.4800
Y:2786991:A:AC	donor_gain	0.4700
Y:2786992:C:CC	donor_gain	0.4700
Y:2787116:A:AT	donor_gain	0.4700
Y:2787146:A:AC	donor_gain	0.4700
Y:2787115:C:CT	donor_gain	0.4600
Y:2786875:T:TC	acceptor_gain	0.4400
Y:2786978:AC:A	donor_gain	0.4400
Y:2786979:CC:C	donor_gain	0.4400
Y:2787267:CCTC:C	acceptor_gain	0.4400
Y:2787268:CTCC:C	acceptor_gain	0.4400
Y:2787269:TCCT:T	acceptor_gain	0.4400
Y:2787114:A:AC	donor_gain	0.4300
Y:2787270:C:G	acceptor_gain	0.4300
Y:2787106:ATC:A	donor_gain	0.4200
Y:2787117:A:AA	donor_gain	0.4100
Y:2787186:T:TA	donor_gain	0.4000

AlphaMissense

1355 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
Y:2787403:G:C	F67L	1.000
Y:2787403:G:T	F67L	1.000
Y:2787405:A:G	F67L	1.000
Y:2787310:C:A	W98C	0.999
Y:2787310:C:G	W98C	0.999
Y:2787312:A:G	W98R	0.999
Y:2787312:A:T	W98R	0.999
Y:2787267:C:G	A113P	0.998
Y:2787311:C:G	W98S	0.998
Y:2787331:G:C	S91R	0.998
Y:2787331:G:T	S91R	0.998
Y:2787333:T:G	S91R	0.998
Y:2787394:C:A	W70C	0.998
Y:2787394:C:G	W70C	0.998
Y:2787396:A:G	W70R	0.998
Y:2787396:A:T	W70R	0.998
Y:2787404:A:G	F67S	0.998
Y:2787277:G:C	F109L	0.997
Y:2787277:G:T	F109L	0.997
Y:2787279:A:G	F109L	0.997
Y:2787286:T:A	K106N	0.997
Y:2787286:T:G	K106N	0.997
Y:2787320:C:T	G95E	0.997
Y:2787379:C:A	R75S	0.997
Y:2787379:C:G	R75S	0.997
Y:2787409:G:C	N65K	0.997
Y:2787409:G:T	N65K	0.997
Y:2787219:A:G	Y129H	0.996
Y:2787246:G:C	H120D	0.996
Y:2787302:A:G	L101P	0.996

dbSNP variants (sampled 300 via entrez): RS1009536101 (Y:2789303 G>C), RS1019031541 (Y:2789154 A>G), RS1019354171 (Y:2787053 G>A), RS1029056107 (Y:2786646 T>G), RS1036584737 (Y:2788929 A>T), RS104894956 (Y:2787278 A>G), RS104894957 (Y:2787426 C>G), RS104894958 (Y:2787327 G>A), RS104894959 (Y:2787334 G>A,C), RS104894964 (Y:2787287 T>A), RS104894965 (Y:2787395 C>T), RS104894966 (Y:2787267 C>T), RS104894967 (Y:2787284 C>G,T), RS104894968 (Y:2787401 A>G), RS104894969 (Y:2787412 C>G,T)

Disease associations

OMIM: gene MIM:480000 | disease phenotypes: MIM:400044, MIM:400045

GenCC curated gene-disease

Disease	Classification	Inheritance
46,XX sex reversal 1	Definitive	X-linked
46,XY sex reversal 1	Definitive	Y-linked inheritance
46,XX ovotesticular disorder of sex development	Supportive	Autosomal dominant
46,XY complete gonadal dysgenesis	Supportive	Autosomal dominant
46,XY partial gonadal dysgenesis	Supportive	Autosomal dominant

Mondo (7): 46,XY sex reversal 1 (MONDO:0020712), 46 XY differences of sex development (MONDO:0020040), 46,XX sex reversal 1 (MONDO:0100250), (MONDO:0010766), 46,XX ovotesticular disorder of sex development (MONDO:0016281), 46,XY complete gonadal dysgenesis (MONDO:0010765), 46,XY partial gonadal dysgenesis (MONDO:0016674)

Orphanet (2): 46,XY complete gonadal dysgenesis (Orphanet:242), 46,XY difference of sex development (Orphanet:98085)

HPO phenotypes

107 total (30 of 107 shown, HPO-id order):

HPO	Term
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000022	Abnormal male internal genitalia morphology
HP:0000026	Male hypogonadism
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000030	Testicular gonadoblastoma
HP:0000032	Abnormal male external genitalia morphology
HP:0000033	Ambiguous genitalia, male
HP:0000037	Male pseudohermaphroditism
HP:0000039	Epispadias
HP:0000041	Chordee
HP:0000044	Hypogonadotropic hypogonadism
HP:0000045	Abnormal scrotum morphology
HP:0000046	Small scrotum
HP:0000047	Hypospadias
HP:0000048	Bifid scrotum
HP:0000054	Micropenis
HP:0000055	Abnormal female external genitalia morphology
HP:0000058	Abnormal labia morphology
HP:0000061	Ambiguous genitalia, female
HP:0000062	Ambiguous genitalia
HP:0000077	Abnormality of the kidney
HP:0000085	Horseshoe kidney
HP:0000098	Tall stature
HP:0000100	Nephrotic syndrome
HP:0000130	Abnormality of the uterus
HP:0000133	Gonadal dysgenesis
HP:0000140	Abnormality of the menstrual cycle
HP:0000142	Abnormal vagina morphology
HP:0000144	Decreased fertility

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D058490	Disorder of Sex Development, 46,XY	C12.050.351.875.253.096; C12.200.706.316.096; C12.800.316.096; C16.131.939.316.096; C19.391.119.096
D006061	Gonadal Dysgenesis, 46,XY	C12.050.351.875.253.096.687; C12.050.351.875.253.309.388; C12.200.706.316.096.687; C12.200.706.316.309.388; C12.800.316.096.687; C12.800.316.309.388; C16.131.939.316.096.687; C16.131.939.316.309.388; C19.391.119.096.687; C19.391.119.309.388
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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
FR900359	increases phosphorylation	1
arsenite	increases methylation	1
cobaltous chloride	affects cotreatment, affects expression	1
lead chloride	affects cotreatment, affects expression	1
cadmium sulfate	affects cotreatment, affects expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases degradation, increases expression, increases reaction	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Cadmium	decreases expression, increases abundance	1
Carmustine	decreases expression	1
Progesterone	increases expression	1
Urethane	decreases expression	1
Cyclosporine	decreases expression	1
Uranium Compounds	increases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Lactic Acid	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_RZ78	XYFMGG16M	Transformed cell line	Sex ambiguous

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT06723938	Not specified	RECRUITING	Phenotypic and Genotypic Characterisation of a Large, Multicentre Italian Cohort of 46, XY DSD Patients