# NM_000054.7(AVPR2):c.579_580del (p.Trp193fs)

https://sugi.bio/variant/avpr2-p-trp193fs

## Summary

**AVPR2 p.Trp193fs (c.579_580del)** is classified **Likely pathogenic** in AVPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-17). No gnomAD frequency available for this variant; Associated with AVPR2-related disorder.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2521156768 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the AVPR2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to AVPR2-related disorder.

*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 | [AVPR2](https://sugi.bio/atlas/gene/AVPR2/) |
| Protein change (HGVS p.) | p.Trp193fs |
| Coding change (HGVS c.) | c.579_580del |
| MANE Select transcript | [NM_000054](https://www.ncbi.nlm.nih.gov/nuccore/NM_000054) |
| dbSNP | [rs2521156768](https://www.ncbi.nlm.nih.gov/snp/rs2521156768/) |
| Variant type | Deletion |
| Location | chrX:153906084-153906085 (GRCh38) |
| ClinVar | [VCV2629646](https://www.ncbi.nlm.nih.gov/clinvar/variation/2629646/) |

**All HGVS expressions:** `LRG_716:g.6112_6113del`, `LRG_716t1:c.579_580del`, `NC_000023.10:g.153171539_153171540del`, `NC_000023.11:g.153906085_153906086del`, `NG_008687.1:g.6112_6113del`, `NG_013220.1:g.25176_25177del`, `NG_013220.2:g.25179_25180del`, `NM_000054.7:c.579_580del`, `NM_001146151.3:c.579_580del`, `NR_027419.2:n.532_533del`

## 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 7.746, GERP 1.87, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 4**, so the transcript is predicted to undergo NMD.
- 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**AVPR2** population constraint: ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (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 **193** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 76.84, 32% of residues very-high.

**44 experimental structure(s)** (PDB): [4JQI](https://www.rcsb.org/structure/4JQI), [6NI2](https://www.rcsb.org/structure/6NI2), [6U1N](https://www.rcsb.org/structure/6U1N), [7BB6](https://www.rcsb.org/structure/7BB6), [7BB7](https://www.rcsb.org/structure/7BB7), [7DF9](https://www.rcsb.org/structure/7DF9).

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

*Describes the biological roles of AVPR2 (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:** AVPR2's established molecular role includes vasopressin receptor activity. In Reactome, AVPR2 is annotated in disease pathway(s) including **Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI)**.

**Disease mechanism (Reactome):** AVPR2 loss or alteration is curated in [Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI)](https://reactome.org/content/detail/R-HSA-9036092).

### Pathways affected {#pathways}

AVPR2 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI)](https://reactome.org/content/detail/R-HSA-9036092) | curated |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [G alpha (s) signalling events](https://reactome.org/content/detail/R-HSA-418555) | curated |
| [Vasopressin regulates renal water homeostasis via Aquaporins](https://reactome.org/content/detail/R-HSA-432040) | curated |
| [Vasopressin-like receptors](https://reactome.org/content/detail/R-HSA-388479) | curated |

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

**Molecular function:** vasopressin receptor activity.

**Biological process:** adenylate cyclase-activating G protein-coupled receptor signaling pathway, negative regulation of cell population proliferation, renal water absorption.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-01-17.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-01-17 |

## Associated conditions {#conditions}

[AVPR2-related disorder](https://sugi.bio/atlas/disease/avpr2-related-disorder/).

**Reported phenotype names (ClinVar):** AVPR2-related disorder, AVPR2-related condition.

## Same-residue context {#hotspot}

Residue **193** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [AVPR2 p.Trp193Ter](/variant/avpr2-p-trp193ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related AVPR2 variant pages (same residue, condition, or type): [AVPR2 p.Ala210fs](/variant/avpr2-p-ala210fs), [AVPR2 p.Gln291fs](/variant/avpr2-p-gln291fs), [AVPR2 p.Leu16fs](/variant/avpr2-p-leu16fs), [AVPR2 p.Leu316fs](/variant/avpr2-p-leu316fs), [AVPR2 p.Trp193Ter](/variant/avpr2-p-trp193ter), [AVPR2 p.Arg104Cys](/variant/avpr2-p-arg104cys), [AVPR2 p.Arg113Trp](/variant/avpr2-p-arg113trp), [AVPR2 p.Arg137His](/variant/avpr2-p-arg137his).

### 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 2629646). 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.*