# NM_000479.5(AMH):c.472_485del (p.Pro158fs)

https://sugi.bio/variant/amh-p-pro158fs

## Summary

**AMH p.Pro158fs (c.472_485del)** is classified **Pathogenic** in AMH (ClinVar, Single submitter, 2 submitters; last evaluated 2024-08-27). Very rare (popmax 0.00205%, nfe).

**At a glance:** Pathogenic · review: Single submitter · rsID rs774592796 · 2 submitters · very rare (popmax 0.00205%, nfe)

## For patients & families {#patients}

This is a change in the AMH gene that is reported as disease-causing, but on limited review, submitted by 2 submitters.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AMH](https://sugi.bio/atlas/gene/AMH/) |
| Protein change (HGVS p.) | p.Pro158fs |
| Coding change (HGVS c.) | c.472_485del |
| MANE Select transcript | [NM_000479](https://www.ncbi.nlm.nih.gov/nuccore/NM_000479) |
| dbSNP | [rs774592796](https://www.ncbi.nlm.nih.gov/snp/rs774592796/) |
| Variant type | Deletion |
| Location | chr19:2250388-2250401 (GRCh38) |
| ClinVar | [VCV8623](https://www.ncbi.nlm.nih.gov/clinvar/variation/8623/) |

**All HGVS expressions:** `NC_000019.10:g.2250396_2250409del`, `NC_000019.9:g.2250395_2250408del`, `NG_012190.1:g.6283_6296del`, `NG_032853.1:g.11023_11036del`, `NM_000479.3:c.472_485del`, `NM_000479.5:c.472_485del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 6.305, GERP 0.79, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.954, pLI 1.0623e-19. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 5**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 23.8**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00205%** (nfe) · FAF95 0.00139% · FAF99 0.00117% · 24/1,169,634 in the highest group · 26/1,589,214 alleles overall — very rare (popmax 0.00205%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00325% | 30,765 |
| European (non-Finnish) (grpmax) | 0.00205% | 48,735 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**AMH** population constraint: LOEUF 1.954, pLI 1.0623e-19, missense-Z -5.9633; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **158** lies in a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 69.40, 16% of residues very-high.

**3 experimental structure(s)** (PDB): [7L0J](https://www.rcsb.org/structure/7L0J), [9BAN](https://www.rcsb.org/structure/9BAN), [9BAO](https://www.rcsb.org/structure/9BAO).

## What this gene does {#gene-function}

*Describes the biological roles of AMH (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** AMH's established molecular role includes signaling receptor binding.


### Pathways affected {#pathways}

AMH participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Signaling by BMP](https://reactome.org/content/detail/R-HSA-201451) | curated |
| [Transcriptional regulation of testis differentiation](https://reactome.org/content/detail/R-HSA-9690406) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** signaling receptor binding, type II transforming growth factor beta receptor binding.

**Biological process:** Mullerian duct regression, positive regulation of gene expression, positive regulation of SMAD protein signal transduction, anti-Mullerian hormone receptor signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-27.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (1992–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1992-12-01 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-08-27 |

**Reported phenotype names (ClinVar):** Persistent mullerian duct syndrome, type I, not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related AMH variant pages (same residue, condition, or type): [AMH p.Pro158Ser](/variant/amh-p-pro158ser), [AMH p.Leu70fs](/variant/amh-p-leu70fs), [AMH p.Gln51fs](/variant/amh-p-gln51fs), [AMH p.Leu112fs](/variant/amh-p-leu112fs), [AMH p.Leu9fs](/variant/amh-p-leu9fs), [AMH p.Arg560fs](/variant/amh-p-arg560fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 8623). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*