Is AVPR2 p.Arg137Cys (c.409C>T) pathogenic?

AVPR2 p.Arg137Cys (c.409C>T) is classified Pathogenic in AVPR2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.8942); Very rare (popmax 0.000335%, nfe); Associated with nephrogenic syndrome of inappropriate antidiuresis.

What condition is associated with AVPR2 p.Arg137Cys (c.409C>T)?

AVPR2 p.Arg137Cys (c.409C>T) is associated with nephrogenic syndrome of inappropriate antidiuresis (ClinVar).

How common is AVPR2 p.Arg137Cys (c.409C>T) in the general population?

AVPR2 p.Arg137Cys (c.409C>T) is very rare (popmax 0.000335%, nfe) (gnomAD).

What do computational predictors say about AVPR2 p.Arg137Cys (c.409C>T)?

AlphaMissense predicts likely pathogenic (score 0.8942) — an in-silico prediction, not a clinical call.

AVPR2 p.Arg137Cys

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.409C>T · rs104894761 · VCV10854

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.8942 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000335%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephrogenic syndrome of inappropriate antidiuresis

Computational evidence

Protein change
AlphaMissense	0.8942	likely pathogenic ✓ concordant with ClinVar
REVEL	0.93	moderately pathogenic-leaning
SaProt	LLR -13.81	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,579 bp · p 0.00022 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000335% European (non-Finnish) · 3/895,622 alleles

Filtering AF 8.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000275% 3/1,089,408 alleles · very rare

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.Arg137Cys
Coding: c.409C>T
MANE Select: NM_000054
dbSNP: rs104894761
Type: single nucleotide variant
Location: chrX:153905915 (GRCh38)
Structure: AlphaFold pLDDT 76.84 · 44 PDB
Residue 137: an α-helix; a disulfide bond; a UniProt-annotated variant site (in nsiad; constitutively active); a UniProt-annotated variant site (in ndi1; fails to activate the adenylyl cyclase system)

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

For Nephrogenic syndrome of inappropriate antidiuresis (Orphanet):

Inheritance: X-linked recessive
Onset: Childhood

Similar variants

AVPR2 p.Arg137His Pathogenic ★★ same residue
AVPR2 p.Arg137Leu Pathogenic same residue
AVPR2 p.Arg137Gly Likely pathogenic ★ same residue
AVPR2 p.Arg104Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
AVPR2 p.Arg202Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
AVPR2 p.Arg337Ter Pathogenic ★★ same condition
AVPR2 p.Tyr128Ser Pathogenic/Likely pathogenic ★★ same condition
AVPR2 p.Val88Met 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-arg137cys (accessed [today's date]).

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