Is AVPR2 p.Leu340Phe (c.1018C>T) pathogenic?

AVPR2 p.Leu340Phe (c.1018C>T) is classified Conflicting classifications of pathogenicity in AVPR2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-06-15). AlphaMissense: likely benign (0.0962); Ultra-rare (popmax 0.0153%, amr); Associated with Inborn genetic diseases.

What condition is associated with AVPR2 p.Leu340Phe (c.1018C>T)?

AVPR2 p.Leu340Phe (c.1018C>T) is associated with Inborn genetic diseases, nephrogenic syndrome of inappropriate antidiuresis, diabetes insipidus, nephrogenic, X-linked (ClinVar).

How common is AVPR2 p.Leu340Phe (c.1018C>T) in the general population?

AVPR2 p.Leu340Phe (c.1018C>T) is ultra-rare (popmax 0.0153%, amr) (gnomAD).

What do computational predictors say about AVPR2 p.Leu340Phe (c.1018C>T)?

AlphaMissense predicts likely benign (score 0.0962) — an in-silico prediction, not a clinical call.

AVPR2 p.Leu340Phe

c.1018C>T · rs781996624 · VCV2577303

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0962 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0153%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0962	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -7.81	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 0.38	GERP -0.56, phastCons 0.99
Regional constraint	o/e 0.80	unconstrained · MANE · 1,579 bp · p 0.00022 · regional, not allelic
Overall
CADD	6.791	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 0.0153% Admixed American · 7/45,867 alleles

Filtering AF 0.00712% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00506%

Overall 0.00101% 11/1,092,049 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0153%	6,552
Remaining individualsnot grpmax-eligible	0.00211%	47,310
European (non-Finnish)	0.000337%	297,103

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.Leu340Phe
Coding: c.1018C>T
MANE Select: NM_000054
dbSNP: rs781996624
Type: single nucleotide variant
Location: chrX:153906630 (GRCh38)
Structure: AlphaFold pLDDT 76.84 · 44 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephrogenic syndrome of inappropriate antidiuresis diabetes insipidus, nephrogenic, X-linked

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-leu340phe (accessed [today's date]).

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