Is AVPR2 p.Leu309= (c.927A>G) pathogenic?

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.

AVPR2 p.Leu309=

Q: What condition is associated with AVPR2 p.Leu309= (c.927A>G)?

AVPR2 p.Leu309= (c.927A>G) is associated with nephrogenic syndrome of inappropriate antidiuresis, diabetes insipidus, nephrogenic, X-linked (ClinVar).

Q: How common is AVPR2 p.Leu309= (c.927A>G) in the general population?

AVPR2 p.Leu309= (c.927A>G) is common (popmax 87.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Nephrogenic syndrome of inappropriate antidiuresis inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.927A>G · rs5201 · VCV254775

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 87.1%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

nephrogenic syndrome of inappropriate antidiuresis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.262	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -3.4, phastCons 1
Overall
CADD	4.101	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 87.1% African / African-American · 49,512/56,850 alleles

Filtering AF 86.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 86.2%

Overall 36.9% 444,438/1,204,137 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	87.1%	1
East Asian	71.6%	1
South Asian	70.5%	1
Admixed American	65.7%	2
Middle Eastern	51%	2
Remaining individualsnot grpmax-eligible	41.5%	2
Ashkenazi Jewishnot grpmax-eligible	36.3%	3
Finnishnot grpmax-eligible	31.4%	3
European (non-Finnish)	28.8%	3
Amishnot grpmax-eligible	7.84%	13

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: AVPR2
Protein: p.Leu309=
Coding: c.927A>G
MANE Select: NM_000054
dbSNP: rs5201
Type: single nucleotide variant
Location: chrX:153906539 (GRCh38)
Structure: AlphaFold pLDDT 76.84 · 44 PDB
Residue 309: a UniProt-annotated variant site (in ndi1); an α-helix

Full AVPR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephrogenic syndrome of inappropriate antidiuresis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: diabetes insipidus, nephrogenic, X-linked

For Nephrogenic syndrome of inappropriate antidiuresis (Orphanet):

Inheritance: X-linked recessive
Onset: Childhood

Similar variants

AVPR2 p.Arg104Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
AVPR2 p.Arg113Trp Pathogenic ★★ same condition
AVPR2 p.Arg137Cys Pathogenic ★★ same condition
AVPR2 p.Arg137His Pathogenic ★★ same condition
AVPR2 p.Arg181Cys Pathogenic ★★ ⚠ same condition
AVPR2 p.Arg202Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
AVPR2 p.Arg337Ter Pathogenic ★★ same condition
AVPR2 p.Asp85Asn Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/avpr2-p-leu309 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown