Is AVPR2 p.Ile221= (c.663C>T) pathogenic?

AVPR2 p.Ile221= (c.663C>T) is classified Likely benign in AVPR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-27). Ultra-rare (popmax 0.0109%, amr); Associated with diabetes insipidus, nephrogenic, X-linked.

What condition is associated with AVPR2 p.Ile221= (c.663C>T)?

AVPR2 p.Ile221= (c.663C>T) is associated with diabetes insipidus, nephrogenic, X-linked, nephrogenic syndrome of inappropriate antidiuresis (ClinVar).

How common is AVPR2 p.Ile221= (c.663C>T) in the general population?

AVPR2 p.Ile221= (c.663C>T) is ultra-rare (popmax 0.0109%, amr) (gnomAD).

How is Arginine vasopressin resistance inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

AVPR2 p.Ile221=

c.663C>T · rs13306212 · VCV727514

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, amr)

Conditions

diabetes insipidus, nephrogenic, X-linked

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 -4.9	GERP -3.7
Overall
CADD	0.321	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0109% Admixed American · 5/45,978 alleles

Filtering AF 0.00426% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0027%

Overall 0.000908% 11/1,211,114 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0109%	9,196
African / African-American	0.00695%	14,383
Remaining individualsnot grpmax-eligible	0.0021%	47,622
European (non-Finnish)	0.000112%	895,399

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.Ile221=
Coding: c.663C>T
MANE Select: NM_000054
dbSNP: rs13306212
Type: single nucleotide variant
Location: chrX:153906169 (GRCh38)
Structure: AlphaFold pLDDT 76.84 · 44 PDB
Residue 221: an α-helix

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

Also linked: nephrogenic syndrome of inappropriate antidiuresis

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.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-ile221 (accessed [today's date]).

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