AMH

Summary

AMH (anti-Mullerian hormone, HGNC:464) is a protein-coding gene on chromosome 19p13.3, encoding Anti-Muellerian hormone (P03971). The anti-Muellerian hormone (AMH) plays an important role in several reproductive functions.

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate N- and C-terminal cleavage products that homodimerize and associate to form a biologically active noncovalent complex. This complex binds to the anti-Mullerian hormone receptor type 2 and causes the regression of Mullerian ducts in the male embryo that would otherwise differentiate into the uterus and fallopian tubes. This protein also plays a role in Leydig cell differentiation and function and follicular development in adult females. Mutations in this gene result in persistent Mullerian duct syndrome.

Source: NCBI Gene 268 — RefSeq curated summary.

At a glance

• Gene–disease (curated): persistent Mullerian duct syndrome (Strong, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 288 total — 18 pathogenic, 11 likely-pathogenic
• GTEx eGene: eQTL in 50 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 8
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.95 (unconstrained)
• MANE Select transcript: NM_000479

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:464
Approved symbol	AMH
Name	anti-Mullerian hormone
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	MIF, MIS
Ensembl gene	ENSG00000104899
Ensembl biotype	protein_coding
OMIM	600957
Entrez	268

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 1 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000221496

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 3: 1, TSL 5: 1

ENST00000221496, ENST00000589313, ENST00000592877

RefSeq mRNA: 1 — MANE Select: NM_000479 NM_000479

CCDS: CCDS12085

Canonical transcript exons

ENST00000221496 — 5 exons

Exon	Start	End
ENSE00000663838	2250337	2250479
ENSE00000663839	2250652	2250760
ENSE00000663841	2251099	2252073
ENSE00002805370	2249323	2249744
ENSE00003664705	2250849	2251008

Expression profiles

Bgee: expression breadth ubiquitous, 160 present calls, max score 91.97.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0385 / max 38.3422, expressed in 5 samples.

Highest expression (Bgee): male germ line stem cell (sensu Vertebrata) in testis, hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex, testis.

Genetic regulation across tissues (GTEx eQTL / sQTL)

AMH is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 50 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 51 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	eqtl	1.7e-118	+0.96	19:2248684:C:T
Esophagus Muscularis	eqtl	1.5e-97	+0.99	19:2248684:C:T
Skin Sun Exposed Lower leg	eqtl	2.1e-94	+0.98	19:2248684:C:T
Cells Cultured fibroblasts	eqtl	5.0e-92	+0.97	19:2248684:C:T
Nerve Tibial	eqtl	4.3e-85	+0.94	19:2248684:C:T
Skin Not Sun Exposed Suprapubic	eqtl	6.2e-78	+1.06	19:2248684:C:T
Thyroid	eqtl	2.0e-75	+0.98	19:2248684:C:T
Esophagus Mucosa	eqtl	3.6e-74	+1.03	19:2248684:C:T
Colon Transverse	eqtl	5.8e-71	+0.93	19:2248684:C:T
Artery Tibial	eqtl	1.7e-63	+0.98	19:2248684:C:T
Colon Sigmoid	eqtl	8.3e-63	+0.94	19:2248684:C:T
Adipose Subcutaneous	eqtl	1.4e-60	+0.94	19:2248684:C:T
Lung	eqtl	1.1e-58	+0.98	19:2248684:C:T
Adipose Visceral Omentum	eqtl	1.1e-55	+0.97	19:2248684:C:T
Breast Mammary Tissue	eqtl	1.2e-51	+0.97	19:2248684:C:T
Esophagus Gastroesophageal Junction	eqtl	3.5e-51	+0.90	19:2248684:C:T
Brain Cortex	eqtl	1.6e-50	+1.29	19:2248684:C:T
Brain Caudate basal ganglia	eqtl	2.9e-48	+1.09	19:2248684:C:T
Stomach	eqtl	1.9e-45	+0.97	19:2248684:C:T
Brain Cerebellar Hemisphere	eqtl	9.7e-43	+1.06	19:2248684:C:T

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
173067	0.0239	3
173065	0.0086	5
173066	0.0060	3

Top tissues by expression

showing 100 of 288 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.97	silver quality
right hemisphere of cerebellum	UBERON:0014890	87.09	gold quality
cerebellar hemisphere	UBERON:0002245	85.93	gold quality
cerebellar cortex	UBERON:0002129	85.33	gold quality
right testis	UBERON:0004534	84.14	gold quality
left testis	UBERON:0004533	83.32	gold quality
adenohypophysis	UBERON:0002196	82.89	gold quality
cerebellum	UBERON:0002037	82.37	gold quality
pituitary gland	UBERON:0000007	81.56	gold quality
testis	UBERON:0000473	81.54	gold quality
right frontal lobe	UBERON:0002810	78.58	gold quality
nucleus accumbens	UBERON:0001882	76.88	gold quality
putamen	UBERON:0001874	74.84	gold quality
caudate nucleus	UBERON:0001873	74.77	gold quality
gastrocnemius	UBERON:0001388	74.26	gold quality
anterior cingulate cortex	UBERON:0009835	73.78	gold quality
cingulate cortex	UBERON:0003027	73.68	gold quality
cortical plate	UBERON:0005343	73.52	gold quality
hindlimb stylopod muscle	UBERON:0004252	73.02	gold quality
Brodmann (1909) area 9	UBERON:0013540	72.87	gold quality
ganglionic eminence	UBERON:0004023	72.55	gold quality
muscle of leg	UBERON:0001383	71.74	gold quality
body of pancreas	UBERON:0001150	70.95	gold quality
amygdala	UBERON:0001876	70.12	gold quality
ventricular zone	UBERON:0003053	69.97	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	69.56	gold quality
muscle layer of sigmoid colon	UBERON:0035805	69.45	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	68.50	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	68.45	gold quality
mucosa of transverse colon	UBERON:0004991	68.18	gold quality
hypothalamus	UBERON:0001898	68.00	gold quality
right uterine tube	UBERON:0001302	67.91	gold quality
brain	UBERON:0000955	67.61	gold quality
muscle organ	UBERON:0001630	67.11	gold quality
stromal cell of endometrium	CL:0002255	66.89	gold quality
pancreatic ductal cell	CL:0002079	66.88	silver quality
spinal cord	UBERON:0002240	66.69	gold quality
forebrain	UBERON:0001890	66.60	gold quality
lower esophagus muscularis layer	UBERON:0035833	66.00	gold quality
lower esophagus	UBERON:0013473	65.90	gold quality
telencephalon	UBERON:0001893	65.37	gold quality
triceps brachii	UBERON:0001509	65.05	gold quality
gluteal muscle	UBERON:0002000	64.95	gold quality
buccal mucosa cell	CL:0002336	64.48	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	64.43	gold quality
neocortex	UBERON:0001950	64.18	gold quality
right ovary	UBERON:0002118	63.93	gold quality
tibial nerve	UBERON:0001323	63.84	gold quality
granulocyte	CL:0000094	63.80	gold quality
transverse colon	UBERON:0001157	63.25	gold quality
embryo	UBERON:0000922	63.04	gold quality
cerebral cortex	UBERON:0000956	62.93	gold quality
body of uterus	UBERON:0009853	62.76	gold quality
small intestine Peyer’s patch	UBERON:0003454	62.66	gold quality
parotid gland	UBERON:0001831	62.48	gold quality
primary visual cortex	UBERON:0002436	62.47	gold quality
sural nerve	UBERON:0015488	62.39	gold quality
ectocervix	UBERON:0012249	62.17	gold quality
left uterine tube	UBERON:0001303	62.16	gold quality
upper lobe of left lung	UBERON:0008952	62.01	gold quality
left ovary	UBERON:0002119	61.91	gold quality
substantia nigra	UBERON:0002038	61.81	gold quality
esophagus	UBERON:0001043	61.77	gold quality
frontal cortex	UBERON:0001870	61.55	gold quality
descending thoracic aorta	UBERON:0002345	60.84	gold quality
colon	UBERON:0001155	60.81	gold quality
small intestine	UBERON:0002108	60.43	gold quality
upper lobe of lung	UBERON:0008948	60.03	gold quality
large intestine	UBERON:0000059	59.98	gold quality
Ammon’s horn	UBERON:0001954	59.94	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	59.87	gold quality
right lobe of thyroid gland	UBERON:0001119	59.77	gold quality
right lobe of liver	UBERON:0001114	59.65	gold quality
midbrain	UBERON:0001891	59.64	gold quality
intestine	UBERON:0000160	59.58	gold quality
right lung	UBERON:0002167	59.56	gold quality
thoracic aorta	UBERON:0001515	59.40	gold quality
inferior olivary complex	UBERON:0002127	59.40	gold quality
body of stomach	UBERON:0001161	59.36	gold quality
anatomical system	UBERON:0000467	59.34	gold quality
temporal lobe	UBERON:0001871	59.27	gold quality
ascending aorta	UBERON:0001496	59.26	gold quality
esophagus mucosa	UBERON:0002469	59.25	gold quality
multicellular organism	UBERON:0000468	59.00	gold quality
material anatomical entity	UBERON:0000465	58.98	gold quality
ovary	UBERON:0000992	58.94	gold quality
pancreas	UBERON:0001264	58.89	gold quality
aorta	UBERON:0000947	58.76	gold quality
skin of leg	UBERON:0001511	58.66	gold quality
popliteal artery	UBERON:0002250	58.46	gold quality
skin of abdomen	UBERON:0001416	58.42	gold quality
tibial artery	UBERON:0007610	58.40	gold quality
left coronary artery	UBERON:0001626	58.32	gold quality
lateral globus pallidus	UBERON:0002476	58.09	gold quality
omental fat pad	UBERON:0010414	58.07	gold quality
peritoneum	UBERON:0002358	58.02	gold quality
left lobe of thyroid gland	UBERON:0001120	57.95	gold quality
endocervix	UBERON:0000458	57.52	gold quality
thyroid gland	UBERON:0002046	57.47	gold quality
right atrium auricular region	UBERON:0006631	57.42	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-124263	yes	5555.97
E-GEOD-134144	yes	4051.06
E-ANND-3	no	0.82

HPA expression

RNA tissue specificity: Group enriched

39 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Pituitary gland	tissue	3.8
Nucleus accumbens	tissue	2.4
Cerebellum	tissue	1.9
Locus coeruleus	tissue	1.4
Hippocampus	tissue	1.3
Postcentral gyrus	tissue	1.3
Testis	tissue	0.7
Cerebral cortex	tissue	0.6
Spinal cord	tissue	0.6
Corpus callosum	tissue	0.6
Olfactory bulb	tissue	0.6
Retrosplenial cortex	tissue	0.6
Basal ganglia	tissue	0.5
Amygdala	tissue	0.5
Midbrain	tissue	0.5
Medulla oblongata	tissue	0.5
Thalamus	tissue	0.5
Superior colliculi	tissue	0.5
Substantia nigra	tissue	0.5
Ventral forebrain	tissue	0.5
Periaqueductal gray	tissue	0.5
Septum	tissue	0.5
Insular cortex	tissue	0.5
Pons	tissue	0.4
Skeletal muscle	tissue	0.4
Putamen	tissue	0.4
Hypothalamus	tissue	0.4
Hippocampal formation	tissue	0.4
Entorhinal cortex	tissue	0.4
Retrosplenial and cingulate cortex	tissue	0.4
Temporal cortex	tissue	0.4
Occipital cortex	tissue	0.4
Prefrontal cortex	tissue	0.3
Vagina	tissue	0.3
Motor cortex	tissue	0.3
Frontal cortex	tissue	0.3
Somatosensory cortex	tissue	0.3
Ovary	tissue	0.1
Choroid plexus	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Caudate nucleus (3.6), Flocculonodular lobe (3.6), Vermis (3.6), Precentral gyrus (3.3), Nucleus basalis of Meynert (2.9).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, ESR2, FOXL2, GATA4, GLI1, NFKB1, NFKB, NR0B1, NR5A1, RELA, SF1, SOX8, SOX9, SRY, VDR, WT1, ZNF354C

miRNA regulators (miRDB)

Targeting AMH by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

7 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3180	98.46	64.68	348
HSA-MIR-3180-3P	98.46	64.68	348
HSA-MIR-615-5P	98.10	63.76	591
HSA-MIR-6131	97.22	66.72	960
HSA-MIR-3663-5P	97.01	64.84	713
HSA-MIR-3178	89.40	60.05	100
HSA-MIR-10394-3P	85.92	60.60	39

Functional genomics

gnomAD constraint: pLI 1.06e-19, LOEUF 1.95, missense Z -5.96 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000221496 — one region, missense o/e 1.27. ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Administration of MIS to male mice induced IEX-1S mRNA in the prostate in vivo, suggesting that MIS may function as an endogenous hormonal regulator of NF-kappaB signaling and growth in the prostate gland. (PMID:11773638)
• poor response in IVF, indicative of a diminished ovarian reserve, is associated with reduced baseline serum AMH concentrations (PMID:12456604)
• Review. The role of AMH in gonadal development and its mutation in the persistent Mullerian duct syndrome is discussed. (PMID:12462075)
• results indicate that serum AMH levels are strongly correlated with ovarian follicular status during the early follicular phase (PMID:12571168)
• Increase of anti-Mullerian hormone(AMH) serum level in polycystic ovary syndrome is consequence of androgen-induced excess in small antral follicle number, and each follicle produces normal amount of AMH. (PMID:14671196)
• Induction of p130 and p107 play an important role in the inhibition of growth of C33A cells by MIS. (PMID:14671316)
• serum anti-Mullerian hormone (AMH) concentrations are elevated in normogonadotropic anovulatory infertile women (WHO 2) women, especially in those patients exhibiting polycystic ovary syndrome (PMID:14715867)
• Anti-Mullerian hormone expression pattern in the human ovary follicle. (PMID:14742691)
• In XXY adolescents, AMH and INHB were undetectable (PMID:15070957)
• Serum AMH concentrations decrease over time both in women presenting with WHO 2 anovulatory infertility and in normal women. Decrease in WHO 2 patients is less pronounced despite distinctly elevated concentrations. May suggest retarded ovarian ageing. (PMID:15217995)
• Recombinant follitropin and chorionic gonadotropin stimulation of the testis dramatically suppresses the secretion of AMH in hypogonadism. (PMID:15536161)
• AMH promoter sequence variations or the previously proposed SF3a2-AMH fusion co-transcripts cannot be responsible for aberrant AMH expression leading to Mullerian duct degradation. (PMID:15550498)
• AMH is also a gonadal tumor suppressor which mediates its effects through a specific type II receptor and the bone morphogenetic protein (BMP)-specific Smad proteins. (PMID:15897891)
• a relative deficiency of AMH in primordial and transitional follicles in ovaries may contribute to disordered early follicle development in polycystic ovary syndrome (PMID:16030171)
• Aggressive granulosa cell tumors(GCTs) retain high GATA-4 expression, whereas larger tumors lose proliferation-suppressing anti-Mullerian hormone expression. High GATA-4 expression in GCTs may serve as marker of poor prognosis. (PMID:16159935)
• Increased MIS production in adolescent girls may represent an early manifestation of polycystic ovary syndrome (PMID:16213847)
• AMH could thus be used as a diagnostic criterion and incorporated as such in the Rotterdam definition of polycystic ovary syndrome. (PMID:16368745)
• MIS could potentially serve as a useful marker for identifying patients at risk for OHSS. (PMID:16566934)
• Mullerian inhibiting substance regulates androgen-induced gene expression and growth in prostate cancer cells through a nuclear factor-kappaB-dependent Smad-independent mechanism. (PMID:16740653)
• Its main physiological role is the induction of regression of Mullerian ducts in male fetuses but it also plays a role in Leydig cell steroidogenesis and in follicular development (PMID:16816803)
• Hence, AMH exhibits a relatively stable expression during the menstrual cycle, making it an attractive determinant of ovarian activity. (PMID:16923748)
• MIS in combination with selective targeted therapies might achieve greater activity against ovarian cancer than the use of each individual agent alone (PMID:17088539)
• serum anti-mullerian hormone (AMH) levels in Polysystic Ovary Syndrome patients were significantly higher than in healthy women (PMID:17335955)
• Polymorphisms in the AMH and AMHR2 genes are associated with follicular phase E(2) levels, suggesting a role for AMH in the regulation of FSH sensitivity in the human ovary. (PMID:17337470)
• Mullerian inhibiting substance has a role in response to ovarian stimulation (PMID:17425826)
• Serum AMH and inhibin B are significantly lower in the men with nonobstructive azoospermia compared to the controls. (PMID:17462637)
• anti-Mullerian hormone expression is stable during the menstrual cycle (PMID:17485437)
• AMH concentrations are increased in peripubertal daughters of polycystic ovary syndrome women (PMID:17488788)
• Oocytes are more likely to be fertilized when follicles are able to make high concentrations of AMH in the follicular fluid. AMH could be a prediction marker for fertilization. (PMID:17543956)
• MIS is the earliest marker to change with agem has it has least intercycle variabilityane has the least intracycle variability; and 4) it may be informative if randomly obtained during the menstrual cycle. {REVIEW] (PMID:17559842)
• Levels of AMH show a statistically significant change during the menstrual cycle and may influence the circulating gonadotropin and steroid hormone levels. (PMID:17603052)
• Infertile patients with endometriosis have a decreased serum anti-Mullerian hormone. (PMID:17624337)
• Granulosa cell production of AMH is augmented by pharmacologically induced increase in the intrafollicular androgen levels. (PMID:17628551)
• Serum anti-Mullerian hormone (AMH) levels differentiate control from subfertile men but not men with different causes of subfertility (PMID:17926161)
• Anti-Mullerian hormone levels in premature ovarian failure patients could identify women with persistent follicles. (PMID:18191888)
• Suggest that there is no significant difference in follicular microenvironment in terms of AMH secretion between GnRH agonist/antagonist protocols and that follicular fluid AMH is a marker that reflects ovarian reserve and response to ovarian stimulation. (PMID:18249372)
• Fluctuations observed are smaller than intercycle variability and thus are not clinically relevant as far as AMH measurements for clinical purposes are concerned. (PMID:18249391)
• The AMH and inhibin B levels on the day of oocyte retrieval are correlated to assisted reproductive outcome. (PMID:18291376)
• preliminary data suggest that AMH levels indicate early ovarian decline among women with longer FMR1 repeat alleles; moreover, AMH appears to be a better marker than FSH in identifying this early decline. (PMID:18310677)
• Review/Meta-Analysis: The role of antimullerian hormone in prediction of outcome after IVF: comparison with the antral follicle count. (PMID:18321493)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	amh	ENSDARG00000014357
mus_musculus	Amh	ENSMUSG00000035262
rattus_norvegicus	Amh	ENSRNOG00000019377

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88006) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 10 distinct phenotype terms.

Mouse phenotype (MP)	Records
secondary sex reversal	2
male pseudohermaphroditism	2
increased Leydig cell number	1
suppressed circulating follicle stimulating hormone level	1
reduced male fertility	1
abnormal secondary sex determination	1
increased ovary weight	1
decreased primordial ovarian follicle number	1
increased tertiary ovarian follicle number	1
increased secondary ovarian follicle number	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	P03972	78.3%	Diamond
Sus scrofa	P79295	78.3%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR6789	ncRNA	102466736
JSRP1	protein-coding	126306
PLEKHJ1	protein-coding	55111
SF3A2	protein-coding	8175
MIR1227	ncRNA	100302283
MIR4321	ncRNA	100423031
DOT1L-AS1	ncRNA	124904611
DOT1L	protein-coding	84444
PEAK3	protein-coding	374872
OAZ1	protein-coding	4946
LINGO3	protein-coding	645191
AP3D1	protein-coding	8943

Protein

Protein identifiers

Anti-Muellerian hormone — P03971 (reviewed: P03971)

Alternative names: Muellerian-inhibiting factor, Muellerian-inhibiting substance

All UniProt accessions (1): P03971

UniProt curated annotations — full annotation on UniProt →

Function. The anti-Muellerian hormone (AMH) plays an important role in several reproductive functions. Anti-Muellerian hormone binds and activates AMHR2, its specific type-II receptor, that heterodimerizes with type-I receptors (ACVR1 and BMPR1A) to regulate target gene expression through downstream SMAD protein signal transduction. Produced and secreted by Sertoli cells of the male fetus, anti-Muellerian hormone induces Muellerian duct regression during male fetal sexual differentiation. In female, it is produced by granulosa cells of the preantral and small antral follicles and acts as a negative regulator of the primordial to primary follicle transition and decreases FSH sensitivity of growing follicles. Also plays a role in Leydig cell differentiation and function.

Subunit / interactions. Homodimer; disulfide-linked. Anti-Muellerian hormone (AMH) is secreted as part of a non-covalent heterotetrameric complex consisting of AMH prodomain and anti-Muellerian hormone homodimers. After proteolytic processing, the dimeric AMH prodomain remains non-covalently associated with the active homodimeric anti-Muellerian hormone, amplifying its biological activity. The AMH prodomain homodimer is displaced upon binding of anti-Muellerian hormone to its receptor.

Subcellular location. Secreted.

Tissue specificity. In ovaries, AMH is detected in granulosa cells of early growing follicles.

Post-translational modifications. The preproprotein is proteolytically processed to generate the AMH prodomain and the anti-Muellerian hormone. Both homodimerize covalently, and homodimers associate to form a non-covalent heterotetrameric complex.

Disease relevance. Persistent Muellerian duct syndrome 1 (PMDS1) [MIM:261550] A form of male pseudohermaphroditism characterized by a failure of Muellerian duct regression in otherwise normal males. The disease is caused by variants affecting the gene represented in this entry.

Induction. Plasma AMH levels in polycystic ovary syndrome (PCOS) patients are two- to threefold higher than in women with normal ovaries.

Similarity. Belongs to the TGF-beta family.

RefSeq proteins (1): NP_000470* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001839	TGF-b_C	Domain
IPR006799	AMH_N	Domain
IPR017948	TGFb_CS	Conserved_site
IPR021203	Muellerian-inhibiting_factor	Family
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF00019, PF04709

UniProt features (64 total): sequence variant 13, mutagenesis site 13, strand 9, disulfide bond 8, region of interest 7, helix 7, glycosylation site 2, signal peptide 1, propeptide 1, site 1, chain 1, turn 1

Structure

Experimental structures (PDB)

3 structures by resolution:

PDB	Title	Method	Resolution (Å)
7L0J	Structure of AMH bound to AMHR2-ECD	X-RAY DIFFRACTION	2.6
9BAO	The Anti-Mullerian Hormone prodomain in complex with the growth factor and 6E11 Fab in C2 …	ELECTRON MICROSCOPY	3.2
9BAN	The Anti-Mullerian Hormone prodomain in complex with the growth factor and 6E11 Fab in C1 …	ELECTRON MICROSCOPY	3.39

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P03971-F1	69.40	0.16

Antibody-complex structures (SAbDab)

2 antibodies co-crystallized with this protein: 9BAN, 9BAO

Human Protein Atlas

Protein class: Predicted secreted proteins, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): aggresome; vesicles

Antibody reliability (HPA): IF approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1)

Position	Role
451–452	cleavage

Disulfide bonds (8)

Type	Positions
Interchain (with c-55 in amh prodomain)	55
Disulfide bond	103–188, 462–526, 488–557, 492–559
Interchain (with c-241 in amh prodomain)	241
Interchain (with c-411 in amh prodomain)	411
Interchain (with c-525 in muellerian-inhibiting factor chain)	525

Glycosylation sites (2)

Type	Positions
N-linked (glcnac…) asparagine	64, 329

Mutagenesis-validated functional residues (13)

Position	Phenotype
55	reduced amh prodomain dimerization; when associated with s-241. impaired amh prodomain dimerization; when associated with s-241 and s-411.
103	loss of signaling activity.
188	loss of signaling activity.
241	reduced amh prodomain dimerization; when associated with s-55. impaired amh prodomain dimerization; when associated with s-55 and s-411.
411	impaired amh prodomain dimerization; when associated with s-55 and s-241.
472	little effect on amh signaling.
478	abolishes amh signaling. does not induce regression of the muellerian duct.
481	shows a slight decrease in amh signaling. affects slightly mullerian duct regression.
481	decreases amh signaling.
484	little effect on amh signaling.
534	abolishes amh signaling.
535	little effect on amh signaling.
546	abolishes amh signaling.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 5; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

ID	Pathway	Evidence
R-HSA-201451	Signaling by BMP	curated
R-HSA-1266738	Developmental Biology	—
R-HSA-162582	Signal Transduction	—
R-HSA-9006936	Signaling by TGFB family members	—
R-HSA-9690406	Transcriptional regulation of testis differentiation	electronic

MSigDB gene sets: 691 (showing top): GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE_BY_P53_CLASS_MEDIATOR, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_ICOSANOID_SECRETION, SHIPP_DLBCL_VS_FOLLICULAR_LYMPHOMA_UP, GOBP_B_CELL_HOMEOSTASIS, GOBP_MYELOID_LEUKOCYTE_MIGRATION, HARRIS_HYPOXIA, GOBP_CELL_CHEMOTAXIS, GOBP_NEGATIVE_REGULATION_OF_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_BY_P53_CLASS_MEDIATOR, GOBP_REGULATION_OF_PROSTAGLANDIN_SECRETION, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_REGULATION_OF_ORGANIC_ACID_TRANSPORT

GO Biological Process (16): ovarian follicle development (GO:0001541), preantral ovarian follicle growth (GO:0001546), Mullerian duct regression (GO:0001880), cell-cell signaling (GO:0007267), gonadal mesoderm development (GO:0007506), sex determination (GO:0007530), sex differentiation (GO:0007548), gonad development (GO:0008406), response to xenobiotic stimulus (GO:0009410), positive regulation of gene expression (GO:0010628), Leydig cell differentiation (GO:0033327), development of primary male sexual characteristics (GO:0046546), positive regulation of SMAD protein signal transduction (GO:0060391), anti-Mullerian hormone receptor signaling pathway (GO:1990262), negative regulation of ovarian follicle development (GO:2000355), cell differentiation (GO:0030154)

GO Molecular Function (6): signaling receptor binding (GO:0005102), type II transforming growth factor beta receptor binding (GO:0005114), transforming growth factor beta receptor binding (GO:0005160), hormone activity (GO:0005179), growth factor activity (GO:0008083), protein binding (GO:0005515)

GO Cellular Component (1): extracellular region (GO:0005576)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Signaling by TGFB family members	1
Developmental Biology	1
Signal Transduction	1

GO top-level categories

37 GO namespaces:

Category	Terms
developmental process involved in reproduction	5
ovarian follicle development	2
male sex differentiation	2
development of primary sexual characteristics	2
receptor ligand activity	2
female gonad development	1
animal gross anatomical part developmental process	1
ovulation cycle process	1
multi-layer follicle stage	1
developmental growth	1
anatomical structure regression	1
cell communication	1
signaling	1
mesoderm development	1
gonad development	1
mesenchyme development	1
animal organ development	1
reproductive structure development	1
response to chemical	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
male gonad development	1
cell differentiation	1
regulation of SMAD protein signal transduction	1
SMAD protein signal transduction	1
positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
positive regulation of intracellular signal transduction	1
cell surface receptor protein serine/threonine kinase signaling pathway	1
negative regulation of developmental process	1
regulation of ovarian follicle development	1
cellular developmental process	1
protein binding	1
transforming growth factor beta receptor binding	1
cytokine receptor binding	1
binding	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 24 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
Mullerian duct regression	BP	direct assay
anti-Mullerian hormone receptor signaling pathway	BP	direct assay
positive regulation of SMAD protein signal transduction	BP	direct assay
positive regulation of gene expression	BP	mutant phenotype
signaling receptor binding	MF	physical interaction
type II transforming growth factor beta receptor binding	MF	direct assay

Protein interactions and networks

STRING

showing 16 of 1,346 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AMH	AMHR2	Q16671	974
AMH	GNRH1	P01148	924
AMH	NR5A1	Q13285	886
AMH	FSHR	P23945	872
AMH	INSL3	P51460	861
AMH	SRY	Q05066	852
AMH	DMRT1	Q9Y5R6	846
AMH	SOX9	P48436	843
AMH	CYP19A1	P11511	838
AMH	GDF9	O60383	832
AMH	NR0B1	P51843	823
AMH	BMP15	O95972	819
AMH	SHBG	P04278	798
AMH	FOXL2	P58012	778
AMH	LHCGR	P22888	727
AMH	STAR	P49675	727

IntAct

Human interaction partners of AMH in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

4 partners by confidence:

Partner	Interaction type	MIscore	Records
PHACTR3	physical association	0.400	1
ARL8B	physical association	0.370	1
ETV5	physical association	0.370	1
ZMAT2	physical association	0.370	1

BioGRID (8 interactions; top human partners by supporting records): ARL8B (Two-hybrid), COPS5 (Affinity Capture-Western), ETV5 (Two-hybrid), FHL3 (Affinity Capture-MS), KIF23 (Affinity Capture-MS), OTUD5 (Affinity Capture-MS), PHACTR3 (Affinity Capture-MS), ZMAT2 (Two-hybrid)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
AMH	up-regulates	AMHR2	binding

Ligand–receptor pairs (CellPhoneDB) (3)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

3 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
AMHR2;BMPR1A	ligand	Signaling by Muellerian-inhibiting factor
AMHR2;BMPR1B	ligand	Signaling by Muellerian-inhibiting factor
AMHR2;ACVR1	ligand	Signaling by Muellerian-inhibiting factor

Disease & clinical

Genetic variants

Variant evidence for AMH: 288 ClinVar records (29 pathogenic / likely pathogenic); 4 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	11
Uncertain significance	153
Likely benign	67
Benign	20

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 29 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
372806	NM_000479.5(AMH):c.208dup (p.Leu70fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2138185	NM_000479.5(AMH):c.1112G>A (p.Trp371Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2736758	NM_000479.5(AMH):c.500A>G (p.Tyr167Cys)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
3583553	NM_000479.5(AMH):c.209del (p.Leu70fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
3583555	NM_000479.5(AMH):c.343_344del (p.Leu115fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
3665082	NM_000479.5(AMH):c.451C>T (p.Pro151Ser)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
3583554	NM_000479.5(AMH):c.301G>A (p.Gly101Arg)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
8623	NM_000479.5(AMH):c.472_485del (p.Pro158fs)	Pathogenic	criteria provided, single submitter	2
8624	NM_000479.5(AMH):c.571C>T (p.Arg191Ter)	Pathogenic	criteria provided, single submitter	2
1323119	NM_000479.5(AMH):c.151del (p.Gln51fs)	Pathogenic	criteria provided, single submitter	1
2169606	NM_000479.5(AMH):c.555+1G>T	Pathogenic	criteria provided, single submitter	1
3605417	NM_000479.5(AMH):c.649dup (p.Gln217fs)	Pathogenic	criteria provided, single submitter	1
3611224	NM_000479.5(AMH):c.1150C>T (p.Gln384Ter)	Pathogenic	criteria provided, single submitter	1
3723227	NM_000479.5(AMH):c.412+3A>G	Pathogenic	criteria provided, single submitter	1
4705424	NM_000479.5(AMH):c.1507T>C (p.Tyr503His)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore AMH’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 19 predictions of 285):

Position(s)	Effect	Δscore	Sites
19:2251090	acceptor_gain	0.9900
19:2249742	donor_gain	0.9800
19:2249657	donor_gain	0.9700
19:2249745–2249746	donor_loss	0.9600	5
19:2250206	donor_gain	0.9500
19:2249746	donor_loss	0.9400
19:2250844	acceptor_gain	0.9300
19:2250761–2250762	donor_loss	0.9100	5
19:2250762	donor_loss	0.9000
19:2250446–2250448	donor_gain	0.8900	2

AlphaMissense

750 missense substitutions predicted likely pathogenic (of 3,464 scored), across 208 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M552	9	0.892	0.985
H506	8	0.967	0.987
F148	8	0.961	0.995
F83	8	0.933	0.985
F290	8	0.922	0.980
F100	8	0.902	0.971
N487	8	0.896	0.997
F235	8	0.874	0.948
C488	7	0.992	0.997
C526	7	0.988	0.994
C492	7	0.987	0.994
C559	7	0.980	0.992
C557	7	0.978	0.993
C462	7	0.976	0.989
C525	7	0.973	0.987
M513	7	0.912	0.965
W140	7	0.906	0.988
D470	7	0.888	0.928
F242	7	0.876	0.956
C188	7	0.869	0.923

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Glioblastoma Multiforme (validation)	favorable	0.000278

Disease associations

OMIM: gene MIM:600957 | disease phenotypes: MIM:261550

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
persistent Mullerian duct syndrome	Strong	Autosomal recessive	3

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

Panel	Rating
Differences in sex development	green

Mondo (1): persistent Mullerian duct syndrome (MONDO:0009857)

Orphanet (2): Rare genetic premature ovarian failure (Orphanet:485382), Persistent Müllerian duct syndrome (Orphanet:2856)

HPO phenotypes

8 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000037	Male pseudohermaphroditism
HP:0003251	Male infertility
HP:0003577	Congenital onset
HP:0008689	Bilateral cryptorchidism
HP:0031103	Decreased circulating antimullerian hormone circulation

GWAS associations

4 associations:

Study	Trait	p-value
GCST003274_9	Pulse pressure	3e-15
GCST007705_47	Pulse pressure	2e-11
GCST006022_13	Pulse pressure	3e-8
GCST010796_2597	Electrocardiogram morphology (amplitude at temporal datapoints)	4e-8

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0005763	pulse pressure measurement
EFO:0004327	electrocardiography

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C536665	Persistent Mullerian duct syndrome *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
Rotenone	decreases expression, increases expression	2
Valproic Acid	decreases expression, increases methylation	2
aristolochic acid I	increases expression	1
MOPP protocol	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sulforaphane	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	increases expression, affects cotreatment	1
ferrous chloride	decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
2-ethyl-5-carboxypentyl phthalate	decreases secretion	1
CD 437	decreases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
pyrimidifen	increases expression	1
prothioconazole	decreases expression	1
monoethyl phthalate	increases secretion	1
Decitabine	decreases expression, affects reaction	1
Lamotrigine	affects cotreatment, increases secretion	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Carbamazepine	decreases expression, increases expression, affects cotreatment, increases secretion	1
Carmustine	decreases expression	1
Cisplatin	decreases expression	1
Dust	decreases expression	1
Estradiol	increases expression	1
Ketoconazole	increases expression	1
Smoke	decreases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

2 trials:

NCT	Phase	Status	Title
NCT01907555	Not specified	COMPLETED	Clinical, Molecular and Physiopathological Study of Cohen Syndrome and Cohen-like Syndromes
NCT03059420	Not specified	RECRUITING	Genetic Studies of Strabismus, Congenital Cranial Dysinnervation Disorders (CCDDs), and Their Associated Anomalies