Is AVPR2 p.Ala42Val (c.125C>T) pathogenic?

AVPR2 p.Ala42Val (c.125C>T) is classified Benign in AVPR2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1021); Low-frequency (popmax 3.36%, afr); Associated with diabetes insipidus, nephrogenic, X-linked.

What condition is associated with AVPR2 p.Ala42Val (c.125C>T)?

AVPR2 p.Ala42Val (c.125C>T) is associated with diabetes insipidus, nephrogenic, X-linked (ClinVar).

How common is AVPR2 p.Ala42Val (c.125C>T) in the general population?

AVPR2 p.Ala42Val (c.125C>T) is low-frequency (popmax 3.36%, 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.Ala42Val (c.125C>T)?

AlphaMissense predicts likely benign (score 0.1021) — an in-silico prediction, not a clinical call.

AVPR2 p.Ala42Val

c.125C>T · rs5198 · VCV368072

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1021 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.36%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

diabetes insipidus, nephrogenic, X-linked

Computational evidence

Protein change
AlphaMissense	0.1021	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -6.71	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 5.8	GERP 0.38, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,579 bp · p 0.00022 · regional, not allelic
Overall
CADD	17.67	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 3.36% African / African-American · 1,938/57,616 alleles

Filtering AF 3.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.19%

Overall 0.178% 2,155/1,210,071 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.36%	30
Remaining individualsnot grpmax-eligible	0.225%	445
Admixed American	0.187%	535
Middle Eastern	0.0467%	2,143
South Asian	0.0088%	11,366
European (non-Finnish)	0.0019%	52,647

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.Ala42Val
Coding: c.125C>T
MANE Select: NM_000054
dbSNP: rs5198
Type: single nucleotide variant
Location: chrX:153905631 (GRCh38)
Structure: AlphaFold pLDDT 76.84 · 44 PDB
Residue 42: an α-helix; a UniProt-annotated variant site (in)

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.Ala42= Benign/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-ala42val (accessed [today's date]).

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