Is AVPR2 p.Arg143His (c.428G>A) pathogenic?

AVPR2 p.Arg143His (c.428G>A) is classified Conflicting classifications of pathogenicity in AVPR2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-07-17). AlphaMissense: likely benign (0.0839); Ultra-rare (popmax 0.0152%, amr); Associated with diabetes insipidus, nephrogenic, X-linked.

What condition is associated with AVPR2 p.Arg143His (c.428G>A)?

AVPR2 p.Arg143His (c.428G>A) is associated with diabetes insipidus, nephrogenic, X-linked (ClinVar).

How common is AVPR2 p.Arg143His (c.428G>A) in the general population?

AVPR2 p.Arg143His (c.428G>A) is ultra-rare (popmax 0.0152%, 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.Arg143His (c.428G>A)?

AlphaMissense predicts likely benign (score 0.0839) — an in-silico prediction, not a clinical call.

AVPR2 p.Arg143His

c.428G>A · rs146238429 · VCV914115

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0839 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0152%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

diabetes insipidus, nephrogenic, X-linked

Computational evidence

Protein change
AlphaMissense	0.0839	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -5.87	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	GERP -3.7, phastCons 0.45
Regional constraint	o/e 0.80	unconstrained · MANE · 1,579 bp · p 0.00022 · regional, not allelic
Overall
CADD	12.91	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 0.0152% Admixed American · 7/46,108 alleles

Filtering AF 0.00709% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00504%

Overall 0.00424% 51/1,203,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0152%	6,587
South Asian	0.0105%	9,500
Remaining individualsnot grpmax-eligible	0.0042%	23,787
European (non-Finnish)	0.00369%	27,137
African / African-American	0.00346%	28,887
Finnishnot grpmax-eligible	0.00261%	38,286

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.Arg143His
Coding: c.428G>A
MANE Select: NM_000054
dbSNP: rs146238429
Type: single nucleotide variant
Location: chrX:153905934 (GRCh38)
Structure: AlphaFold pLDDT 76.84 · 44 PDB
Residue 143: 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.Arg143Cys Uncertain significance ★ ⚠ 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-arg143his (accessed [today's date]).

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