Is AVPR2 p.Pro349Leu (c.1046C>T) pathogenic?

AVPR2 p.Pro349Leu (c.1046C>T) is classified Uncertain significance in AVPR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-21). AlphaMissense: likely benign (0.087); Very rare (popmax 0.00654%, amr); Associated with Inborn genetic diseases.

What condition is associated with AVPR2 p.Pro349Leu (c.1046C>T)?

AVPR2 p.Pro349Leu (c.1046C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AVPR2 p.Pro349Leu (c.1046C>T) in the general population?

AVPR2 p.Pro349Leu (c.1046C>T) is very rare (popmax 0.00654%, amr) (gnomAD).

What do computational predictors say about AVPR2 p.Pro349Leu (c.1046C>T)?

AlphaMissense predicts likely benign (score 0.087) — an in-silico prediction, not a clinical call.

AVPR2 p.Pro349Leu

c.1046C>T · rs140075460 · VCV2960999

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.087 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00654%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.087	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -7.50	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 0.55	GERP 0.44
Regional constraint	o/e 0.80	unconstrained · MANE · 1,579 bp · p 0.00022 · regional, not allelic
Overall
CADD	7.374	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00654% Admixed American · 3/45,898 alleles

Filtering AF 0.00173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00088%

Overall 0.000662% 8/1,209,212 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00654%	15,299
East Asian	0.00296%	33,759
European (non-Finnish)	0.000447%	223,488

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.Pro349Leu
Coding: c.1046C>T
MANE Select: NM_000054
dbSNP: rs140075460
Type: single nucleotide variant
Location: chrX:153906658 (GRCh38)
Structure: AlphaFold pLDDT 76.84 · 44 PDB
Residue 349: a β-strand; the 'disordered' region

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

Similar variants

AVPR2 p.Pro244Thr Uncertain significance ★★ ⚠ same condition
AVPR2 p.Ala223Thr Benign/Likely benign ★★ same condition
AVPR2 p.Gly257Ser Benign/Likely benign ★★ same condition
AVPR2 p.Gly352Asp Benign/Likely benign ★★ same condition
AVPR2 p.Pro286Leu Likely pathogenic ★ same condition
AVPR2 p.Ala114Thr Uncertain significance ★ ⚠ same condition
AVPR2 p.Ala179Thr Uncertain significance ★ ⚠ same condition
AVPR2 p.Ala305Glu Uncertain significance ★ ⚠ 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-pro349leu (accessed [today's date]).

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