46,XY sex reversal 6

Summary

46,XY sex reversal 6 (MONDO:0013410) is a disease caused by MAP3K1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: MAP3K1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 219

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	46,XY sex reversal 6
Mondo ID	MONDO:0013410
OMIM	613762
DOID	DOID:0111769
UMLS	C3151064
MedGen	462414
GARD	0015703
Is cancer (heuristic)	no

Also known as: 46,XY sex reversal 6 · 46,XY Sex reversal type 6 · 46XY sex reversal 6 · SRXY6

Data availability: 219 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › hypogonadism › gonadal dysgenesis › 46,XY complete gonadal dysgenesis › 46,XY sex reversal 6

Related subtypes (11): 46,XY sex reversal 4, 46,XY sex reversal 7, 46,XY sex reversal 2, 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome, 46,XY sex reversal 3, 46,XY sex reversal 5, 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency, 46,XY sex reversal 9, 46,XY sex reversal 10, 46,XY sex reversal 1, 46,XY sex reversal 11

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

219 retrieved; paginated sample, class counts are floors:

72 uncertain significance, 61 likely benign, 45 benign, 19 conflicting classifications of pathogenicity, 11 benign/likely benign, 6 pathogenic, 4 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2745804	NM_005921.2(MAP3K1):c.1348A>G (p.Met450Val)	MAP3K1	Pathogenic	criteria provided, single submitter
30144	NM_005921.2(MAP3K1):c.634-8T>A	MAP3K1	Pathogenic	criteria provided, single submitter
30146	NM_005921.2(MAP3K1):c.566T>C (p.Leu189Pro)	MAP3K1	Pathogenic	criteria provided, single submitter
30147	NM_005921.2(MAP3K1):c.566T>G (p.Leu189Arg)	MAP3K1	Pathogenic	no assertion criteria provided
430732	NM_005921.2(MAP3K1):c.1760T>A (p.Leu587His)	MAP3K1	Pathogenic	no assertion criteria provided
471688	NM_005921.2(MAP3K1):c.1016G>A (p.Arg339Gln)	MAP3K1	Pathogenic	criteria provided, single submitter
649338	NM_005921.2(MAP3K1):c.556A>G (p.Arg186Gly)	MAP3K1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2507001	NM_005921.2(MAP3K1):c.3964T>G (p.Phe1322Val)	MAP3K1	Likely pathogenic	criteria provided, single submitter
268092	NM_005921.2(MAP3K1):c.1923G>A (p.Met641Ile)	MAP3K1	Likely pathogenic	no assertion criteria provided
430731	NM_005921.2(MAP3K1):c.566T>A (p.Leu189Gln)	MAP3K1	Likely pathogenic	criteria provided, single submitter
4538420	NM_005921.2(MAP3K1):c.2370-1G>C	MAP3K1	Likely pathogenic	no assertion criteria provided
1033045	NM_005921.2(MAP3K1):c.44C>G (p.Pro15Arg)	LOC129993918	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1601738	NM_005921.2(MAP3K1):c.5CGG[5] (p.Ala5dup)	LOC129993918	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2417555	NM_005921.2(MAP3K1):c.293C>G (p.Ala98Gly)	LOC129993918	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2546546	NM_005921.2(MAP3K1):c.185T>G (p.Leu62Arg)	LOC129993918	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2801897	NM_005921.2(MAP3K1):c.228G>C (p.Gln76His)	LOC129993918	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3891624	NM_005921.2(MAP3K1):c.152G>C (p.Gly51Ala)	LOC129993918	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
435820	NM_005921.2(MAP3K1):c.458C>T (p.Pro153Leu)	LOC129993918	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1125541	NM_005921.2(MAP3K1):c.917G>A (p.Arg306His)	MAP3K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1521343	NM_005921.2(MAP3K1):c.3070A>C (p.Lys1024Gln)	MAP3K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1652628	NM_005921.2(MAP3K1):c.2479G>A (p.Val827Ile)	MAP3K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2063183	NM_005921.2(MAP3K1):c.476C>T (p.Pro159Leu)	MAP3K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216959	NM_005921.2(MAP3K1):c.770C>T (p.Pro257Leu)	MAP3K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2343812	NM_005921.2(MAP3K1):c.959A>G (p.Gln320Arg)	MAP3K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
539063	NM_005921.2(MAP3K1):c.934A>T (p.Met312Leu)	MAP3K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
590937	NM_005921.2(MAP3K1):c.548G>A (p.Arg183Gln)	MAP3K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
773980	NM_005921.2(MAP3K1):c.2431A>G (p.Met811Val)	MAP3K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
833601	NM_005921.2(MAP3K1):c.2696A>G (p.Asn899Ser)	MAP3K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
931588	NM_005921.2(MAP3K1):c.1510G>A (p.Glu504Lys)	MAP3K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
982900	NM_005921.2(MAP3K1):c.3857A>T (p.Glu1286Val)	MAP3K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MAP3K1	Definitive	Autosomal dominant	46,XY sex reversal 6	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAP3K1	Orphanet:242	46,XY complete gonadal dysgenesis
MAP3K1	Orphanet:251510	46,XY partial gonadal dysgenesis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MAP3K1	HGNC:6848	ENSG00000095015	Q13233	Mitogen-activated protein kinase kinase kinase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAP3K1	Mitogen-activated protein kinase kinase kinase 1	Component of a protein kinase signal transduction cascade.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MAP3K1	Kinase	yes	2.7.11.25	Prot_kinase_dom, Znf_RING, Znf_SWIM

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
skin of hip	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAP3K1	264	ubiquitous	marker	buccal mucosa cell, upper leg skin, skin of hip

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAP3K1	4,414

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MAP3K1	Q13233	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TRAF6 mediated NF-kB activation	1	456.8×	0.008	MAP3K1
FCERI mediated MAPK activation	1	346.1×	0.008	MAP3K1
Fc epsilon receptor (FCERI) signaling	1	271.9×	0.008	MAP3K1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1	253.8×	0.008	MAP3K1
Toll Like Receptor 10 (TLR10) Cascade	1	215.5×	0.008	MAP3K1
Toll Like Receptor 5 (TLR5) Cascade	1	215.5×	0.008	MAP3K1
MyD88 cascade initiated on plasma membrane	1	203.9×	0.008	MAP3K1
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1	190.3×	0.008	MAP3K1
MyD88 dependent cascade initiated on endosome	1	190.3×	0.008	MAP3K1
Toll Like Receptor 7/8 (TLR7/8) Cascade	1	184.2×	0.008	MAP3K1
Toll Like Receptor 9 (TLR9) Cascade	1	175.7×	0.008	MAP3K1
Toll Like Receptor TLR6:TLR2 Cascade	1	175.7×	0.008	MAP3K1
Toll Like Receptor 2 (TLR2) Cascade	1	173.0×	0.008	MAP3K1
Toll Like Receptor TLR1:TLR2 Cascade	1	167.9×	0.008	MAP3K1
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1	152.3×	0.008	MAP3K1
Toll Like Receptor 4 (TLR4) Cascade	1	131.3×	0.009	MAP3K1
Toll-like Receptor Cascades	1	124.1×	0.009	MAP3K1
Innate Immune System	1	25.5×	0.041	MAP3K1
Immune System	1	13.0×	0.077	MAP3K1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Fc-epsilon receptor signaling pathway	1	732.7×	0.004	MAP3K1
cellular response to mechanical stimulus	1	216.1×	0.007	MAP3K1
protein phosphorylation	1	68.0×	0.015	MAP3K1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MAP3K1	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP3K1	31	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	MAP3K1
SORAFENIB	4	MAP3K1
RUXOLITINIB	4	MAP3K1
REGORAFENIB	4	MAP3K1
BARICITINIB	4	MAP3K1
BOSUTINIB	4	MAP3K1
TOVORAFENIB	4	MAP3K1
RIBOCICLIB	4	MAP3K1
PAZOPANIB	4	MAP3K1
DASATINIB	4	MAP3K1
ERLOTINIB	4	MAP3K1
CRIZOTINIB	4	MAP3K1
ICOTINIB	3	MAP3K1
TESEVATINIB	3	MAP3K1
LESTAURTINIB	3	MAP3K1
TG100-115	2	MAP3K1
SCH-900776	2	MAP3K1
OSI-632	2	MAP3K1
GOLVATINIB	2	MAP3K1
RG-547	2	MAP3K1
DANUSERTIB	2	MAP3K1
AT-9283	2	MAP3K1
PELITINIB	2	MAP3K1
GSK-461364	1	MAP3K1
KW-2449	1	MAP3K1
AV-412 FREE BASE	1	MAP3K1
LY-3009120	1	MAP3K1
PF-03814735	1	MAP3K1
CYC-116	1	MAP3K1
AST-487	1	MAP3K1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MAP3K1	167	Binding:165, ADMET:1, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MAP3K1	2.7.11.25	mitogen-activated protein kinase kinase kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
MAP3K1	167

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PONATINIB	4	MAP3K1
SORAFENIB	4	MAP3K1
RUXOLITINIB	4	MAP3K1
REGORAFENIB	4	MAP3K1
BARICITINIB	4	MAP3K1
BOSUTINIB	4	MAP3K1
TOVORAFENIB	4	MAP3K1
RIBOCICLIB	4	MAP3K1
PAZOPANIB	4	MAP3K1
DASATINIB	4	MAP3K1
ERLOTINIB	4	MAP3K1
CRIZOTINIB	4	MAP3K1
ICOTINIB	3	MAP3K1
TESEVATINIB	3	MAP3K1
LESTAURTINIB	3	MAP3K1
TG100-115	2	MAP3K1
SCH-900776	2	MAP3K1
OSI-632	2	MAP3K1
GOLVATINIB	2	MAP3K1
RG-547	2	MAP3K1
DANUSERTIB	2	MAP3K1
AT-9283	2	MAP3K1
PELITINIB	2	MAP3K1
GSK-461364	1	MAP3K1
KW-2449	1	MAP3K1
AV-412 FREE BASE	1	MAP3K1
LY-3009120	1	MAP3K1
PF-03814735	1	MAP3K1
CYC-116	1	MAP3K1
AST-487	1	MAP3K1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MAP3K1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.