# NM_000054.7(AVPR2):c.927A>G (p.Leu309=)

https://sugi.bio/variant/avpr2-p-leu309

## Summary

**AVPR2 p.Leu309= (c.927A>G)** is classified **Benign** in AVPR2 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). Common (popmax 87.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with nephrogenic syndrome of inappropriate antidiuresis.

**At a glance:** Benign · review: Multiple submitters · rsID rs5201 · 11 submitters · 2 linked conditions · common (popmax 87.1%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the AVPR2 gene that is classified as benign — not considered disease-causing, submitted by 11 submitters, and is linked to nephrogenic syndrome of inappropriate antidiuresis.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | X-linked recessive |
| Age of onset (of this condition) | Childhood |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | AVPR2 is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010306/index) · [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.Leu309= |
| Coding change (HGVS c.) | c.927A>G |
| MANE Select transcript | [NM_000054](https://www.ncbi.nlm.nih.gov/nuccore/NM_000054) |
| dbSNP | [rs5201](https://www.ncbi.nlm.nih.gov/snp/rs5201/) |
| Variant type | single nucleotide variant |
| Location | chrX:153906539-153906539 (GRCh38) |
| ClinVar | [VCV254775](https://www.ncbi.nlm.nih.gov/clinvar/variation/254775/) |

**All HGVS expressions:** `LRG_716:g.6566A>G`, `LRG_716t1:c.927A>G`, `NC_000023.10:g.153171993A>G`, `NC_000023.11:g.153906539A>G`, `NG_008687.1:g.6566A>G`, `NG_013220.1:g.24722T>C`, `NM_000054.7:c.927A>G`, `NM_001146151.3:c.*103A>G`, `NR_027419.2:n.880A>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 87.1%, afr) — too common for a highly-penetrant pathogenic allele.

- **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 2.026, GERP -3.41, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 4.101**. 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** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **87.1%** (afr) · FAF95 86.4% · FAF99 86.2% · 49,512/56,850 in the highest group · 444,438/1,204,137 alleles overall — common (popmax 87.1%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 87.1% | 1 |
| East Asian | 71.6% | 1 |
| South Asian | 70.5% | 1 |
| Admixed American | 65.7% | 2 |
| Middle Eastern | 51% | 2 |
| Remaining individuals (not grpmax-eligible) | 41.5% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 36.3% | 3 |
| Finnish (not grpmax-eligible) | 31.4% | 3 |
| European (non-Finnish) | 28.8% | 3 |
| Amish (not grpmax-eligible) | 7.84% | 13 |

*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 **309** lies in a UniProt-annotated variant site (in ndi1); an α-helix.

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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** unanimous (12/12 Benign).

**Submission history:** 12 submissions (2017–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2017-07-26 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Benign | no assertion criteria provided | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-11-10 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-28 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-03-09 |

## Associated conditions {#conditions}

[nephrogenic syndrome of inappropriate antidiuresis](https://sugi.bio/atlas/disease/nephrogenic-syndrome-of-inappropriate-antidiuresis/), [diabetes insipidus, nephrogenic, X-linked](https://sugi.bio/atlas/disease/diabetes-insipidus-nephrogenic-x-linked/).

**Reported phenotype names (ClinVar):** Nephrogenic syndrome of inappropriate antidiuresis, not specified, Diabetes insipidus, nephrogenic, X-linked, not provided, AllHighlyPenetrant, none provided, Nephrogenic Diabetes Insipidus, Type I.

## Similar variants {#similar}

Related AVPR2 variant pages (same residue, condition, or type): [AVPR2 p.Arg104Cys](/variant/avpr2-p-arg104cys), [AVPR2 p.Arg113Trp](/variant/avpr2-p-arg113trp), [AVPR2 p.Arg137Cys](/variant/avpr2-p-arg137cys), [AVPR2 p.Arg137His](/variant/avpr2-p-arg137his), [AVPR2 p.Arg181Cys](/variant/avpr2-p-arg181cys), [AVPR2 p.Arg202Cys](/variant/avpr2-p-arg202cys), [AVPR2 p.Arg337Ter](/variant/avpr2-p-arg337ter), [AVPR2 p.Asp85Asn](/variant/avpr2-p-asp85asn).

### 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 254775). 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.*