Is AVPR2 p.Ala147Val (c.440C>T) pathogenic?

AVPR2 p.Ala147Val (c.440C>T) is classified Benign in AVPR2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1764); Common (popmax 5.2%, afr) — too common for a highly-penetrant pathogenic allele; Associated with diabetes insipidus, nephrogenic, X-linked.

What condition is associated with AVPR2 p.Ala147Val (c.440C>T)?

AVPR2 p.Ala147Val (c.440C>T) is associated with diabetes insipidus, nephrogenic, X-linked (ClinVar).

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.Ala147Val (c.440C>T)?

AlphaMissense predicts likely benign (score 0.1764) — an in-silico prediction, not a clinical call.

AVPR2 p.Ala147Val

Q: How common is AVPR2 p.Ala147Val (c.440C>T) in the general population?

AVPR2 p.Ala147Val (c.440C>T) is common (popmax 5.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.440C>T · rs5200 · VCV254774

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1764 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.2%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

diabetes insipidus, nephrogenic, X-linked

Computational evidence

Protein change
AlphaMissense	0.1764	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -7.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.9	GERP 0.55, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,579 bp · p 0.00022 · regional, not allelic
Overall
CADD	21.1	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 5.2% African / African-American · 3,003/57,799 alleles

Filtering AF 5.04% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.98%

Overall 0.291% 3,504/1,203,388 alleles · common exomes 1,761/1,089,626 · genomes 1,743/113,762 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.2%	19
Remaining individualsnot grpmax-eligible	0.433%	231
Admixed American	0.384%	261
Middle Eastern	0.23%	436
East Asian	0.0414%	2,415
South Asian	0.0105%	9,500
European (non-Finnish)	0.00983%	10,176

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.Ala147Val
Coding: c.440C>T
MANE Select: NM_000054
dbSNP: rs5200
Type: single nucleotide variant
Location: chrX:153905946 (GRCh38)
Structure: AlphaFold pLDDT 76.84 · 44 PDB
Residue 147: a turn; 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.Ala147= 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-ala147val (accessed [today's date]).

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