Is AVPR2 p.Arg248Cys (c.742C>T) pathogenic?

AVPR2 p.Arg248Cys (c.742C>T) is classified Conflicting classifications of pathogenicity in AVPR2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-03-18). AlphaMissense: likely benign (0.1643); Ultra-rare (popmax 0.0348%, amr); Associated with diabetes insipidus, nephrogenic, X-linked.

What condition is associated with AVPR2 p.Arg248Cys (c.742C>T)?

AVPR2 p.Arg248Cys (c.742C>T) is associated with diabetes insipidus, nephrogenic, X-linked (ClinVar).

How common is AVPR2 p.Arg248Cys (c.742C>T) in the general population?

AVPR2 p.Arg248Cys (c.742C>T) is ultra-rare (popmax 0.0348%, amr) (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.Arg248Cys (c.742C>T)?

AlphaMissense predicts likely benign (score 0.1643) — an in-silico prediction, not a clinical call.

AVPR2 p.Arg248Cys

c.742C>T · rs782516523 · VCV914118

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1643 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0348%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

diabetes insipidus, nephrogenic, X-linked

Computational evidence

Protein change
AlphaMissense	0.1643	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -9.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -3.6, phastCons 0.075
Regional constraint	o/e 0.80	unconstrained · MANE · 1,579 bp · p 0.00022 · regional, not allelic
Overall
CADD	11.29	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 0.0348% Admixed American · 16/45,916 alleles

Filtering AF 0.0218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.0161% 194/1,206,380 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0348%	2,870
Remaining individualsnot grpmax-eligible	0.0274%	3,648
European (non-Finnish)	0.0179%	5,571
East Asian	0.00592%	16,894
Finnishnot grpmax-eligible	0.00214%	46,637
South Asian	0.00176%	56,921
African / African-American	0.00174%	57,457

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.Arg248Cys
Coding: c.742C>T
MANE Select: NM_000054
dbSNP: rs782516523
Type: single nucleotide variant
Location: chrX:153906248 (GRCh38)
Structure: AlphaFold pLDDT 76.84 · 44 PDB
Residue 248: a UniProt-annotated variant site (in ndi1); the 'disordered' region

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.Arg248= 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.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-arg248cys (accessed [today's date]).

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