Is AVPR2 p.Arg181Cys (c.541C>T) pathogenic?

AVPR2 p.Arg181Cys (c.541C>T) is classified Pathogenic in AVPR2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-31). AlphaMissense: ambiguous (0.3768); Very rare (popmax 9.12e-05%); Associated with diabetes insipidus, nephrogenic, X-linked.

What condition is associated with AVPR2 p.Arg181Cys (c.541C>T)?

AVPR2 p.Arg181Cys (c.541C>T) is associated with diabetes insipidus, nephrogenic, X-linked (ClinVar).

How common is AVPR2 p.Arg181Cys (c.541C>T) in the general population?

AVPR2 p.Arg181Cys (c.541C>T) is very rare (popmax 9.12e-05%) (gnomAD).

How is Arginine vasopressin resistance inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about AVPR2 p.Arg181Cys (c.541C>T)?

AlphaMissense predicts ambiguous (score 0.3768) — an in-silico prediction, not a clinical call.

AVPR2 p.Arg181Cys

c.541C>T · rs104894757 · VCV10850

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3768 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.12e-05%)

Conditions

diabetes insipidus, nephrogenic, X-linked

Computational evidence

Protein change
AlphaMissense	0.3768	ambiguous
REVEL	0.639	indeterminate
SaProt	LLR -8.19	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.53, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,579 bp · p 0.00022 · regional, not allelic
Overall
CADD	23.8	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 9.12e-05%

Overall 9.12e-05% 1/1,096,573 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.Arg181Cys
Coding: c.541C>T
MANE Select: NM_000054
dbSNP: rs104894757
Type: single nucleotide variant
Location: chrX:153906047 (GRCh38)
Structure: AlphaFold pLDDT 76.84 · 44 PDB
Residue 181: a β-strand; a disulfide bond; a UniProt-annotated variant site (in ndi1)

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

Disease context

diabetes insipidus, nephrogenic, X-linked — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Arginine vasopressin resistance (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

AVPR2 p.Arg181His Likely benign ★★ ⚠ same residue
AVPR2 p.Arg104Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
AVPR2 p.Arg113Trp Pathogenic ★★ same condition
AVPR2 p.Arg137His Pathogenic ★★ same condition
AVPR2 p.Arg202Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
AVPR2 p.Arg337Ter Pathogenic ★★ same condition
AVPR2 p.Asp85Asn Pathogenic ★★ same condition
AVPR2 p.Gly107Glu Likely 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-arg181cys (accessed [today's date]).

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