Is AVPR2 p.Arg143Cys (c.427C>T) pathogenic?

AVPR2 p.Arg143Cys (c.427C>T) is classified Uncertain significance in AVPR2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-11-19). AlphaMissense: likely benign (0.217); Very rare (popmax 0.00346%, afr); Associated with nephrogenic diabetes insipidus.

What condition is associated with AVPR2 p.Arg143Cys (c.427C>T)?

AVPR2 p.Arg143Cys (c.427C>T) is associated with nephrogenic diabetes insipidus (ClinVar).

How common is AVPR2 p.Arg143Cys (c.427C>T) in the general population?

AVPR2 p.Arg143Cys (c.427C>T) is very rare (popmax 0.00346%, afr) (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.Arg143Cys (c.427C>T)?

AlphaMissense predicts likely benign (score 0.217) — an in-silico prediction, not a clinical call.

AVPR2 p.Arg143Cys

c.427C>T · rs1450278600 · VCV1804775

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.217 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00346%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephrogenic diabetes insipidus

Computational evidence

Protein change
AlphaMissense	0.217	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -10.28	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
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	21.2	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 0.00346% African / African-American · 2/57,767 alleles

Filtering AF 0.000574% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000342%

Overall 0.0015% 18/1,203,175 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0181%	5,512
Remaining individualsnot grpmax-eligible	0.0042%	23,789
African / African-Americangrpmax	0.00346%	28,884
South Asian	0.00175%	57,000
European (non-Finnish)	0.00101%	99,501

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg143Cys
Coding: c.427C>T
MANE Select: NM_000054
dbSNP: rs1450278600
Type: single nucleotide variant
Location: chrX:153905933 (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

nephrogenic diabetes insipidus — 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.Arg143His Conflicting classifications of pathogenicity ★ ⚠ same residue
AVPR2 p.Arg104Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
AVPR2 p.Arg137His Pathogenic ★★ same condition
AVPR2 p.Pro322Leu Pathogenic/Likely pathogenic ★★ same condition
AVPR2 p.Tyr205Cys Pathogenic/Likely pathogenic ★★ same condition
AVPR2 p.Ala285Pro Likely pathogenic ★ same condition
AVPR2 p.Arg137Gly Likely pathogenic ★ same condition
AVPR2 p.Arg143delinsTrpTrpAlaCysMetProProProThrTer Pathogenic ★ same residue

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-arg143cys (accessed [today's date]).

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