Is AVPR2 p.Ala4= (c.12G>A) pathogenic?

AVPR2 p.Ala4= (c.12G>A) is classified Benign/Likely benign in AVPR2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-28). Low-frequency (popmax 1.53%, afr); Associated with nephrogenic syndrome of inappropriate antidiuresis.

How common is AVPR2 p.Ala4= (c.12G>A) in the general population?

AVPR2 p.Ala4= (c.12G>A) is low-frequency (popmax 1.53%, afr) (gnomAD).

AVPR2 p.Ala4=

Q: What condition is associated with AVPR2 p.Ala4= (c.12G>A)?

AVPR2 p.Ala4= (c.12G>A) is associated with nephrogenic syndrome of inappropriate antidiuresis, diabetes insipidus, nephrogenic, X-linked (ClinVar).

Q: How is Nephrogenic syndrome of inappropriate antidiuresis inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.12G>A · rs61748993 · VCV254771

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.53%, afr)

Conditions

nephrogenic syndrome of inappropriate antidiuresis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.7	GERP -1.8
Overall
CADD	0.214	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.53% African / African-American · 878/57,418 alleles

Filtering AF 1.45% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.41%

Overall 0.0814% 985/1,210,577 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.53%	65
Middle Eastern	0.208%	480
Remaining individualsnot grpmax-eligible	0.0882%	1,133
Admixed American	0.0587%	1,702
South Asian	0.00527%	18,958
European (non-Finnish)	0.0029%	34,430

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.Ala4=
Coding: c.12G>A
MANE Select: NM_000054
dbSNP: rs61748993
Type: single nucleotide variant
Location: chrX:153905157 (GRCh38)
Structure: AlphaFold pLDDT 76.84 · 44 PDB
Residue 4: the 'disordered' region

Full AVPR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephrogenic syndrome of inappropriate antidiuresis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: diabetes insipidus, nephrogenic, X-linked

For Nephrogenic syndrome of inappropriate antidiuresis (Orphanet):

Inheritance: X-linked recessive
Onset: Childhood

Similar variants

AVPR2 p.Arg104Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
AVPR2 p.Arg113Trp Pathogenic ★★ same condition
AVPR2 p.Arg137Cys 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-ala4 (accessed [today's date]).

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