Is AVPR2 p.Arg181His (c.542G>A) pathogenic?

AVPR2 p.Arg181His (c.542G>A) is classified Likely benign in AVPR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.1372); Rare (popmax 0.175%, afr).

How common is AVPR2 p.Arg181His (c.542G>A) in the general population?

AVPR2 p.Arg181His (c.542G>A) is rare (popmax 0.175%, afr) (gnomAD).

What do computational predictors say about AVPR2 p.Arg181His (c.542G>A)?

AlphaMissense predicts likely benign (score 0.1372) — an in-silico prediction, not a clinical call.

AVPR2 p.Arg181His

c.542G>A · rs141876414 · VCV722450

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1372 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.175%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1372	likely benign
REVEL	0.421	indeterminate
SaProt	LLR -8.63	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,579 bp · p 0.00022 · regional, not allelic
Overall
CADD	22.6	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 0.175% African / African-American · 101/57,746 alleles

Filtering AF 0.147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.137%

Overall 0.0109% 132/1,210,174 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.175%	572
Remaining individualsnot grpmax-eligible	0.0084%	11,908
Admixed American	0.00651%	15,359
South Asian	0.00351%	28,487
European (non-Finnish)	0.00246%	40,700

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.Arg181His
Coding: c.542G>A
MANE Select: NM_000054
dbSNP: rs141876414
Type: single nucleotide variant
Location: chrX:153906048 (GRCh38)
Structure: AlphaFold pLDDT 76.84 · 44 PDB
Residue 181: a β-strand; a disulfide bond; a UniProt-annotated variant site (in ndi1)

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

Similar variants

AVPR2 p.Arg181Cys Pathogenic ★★ ⚠ same residue
AVPR2 p.Arg104Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
AVPR2 p.Arg113Trp Pathogenic ★★ same type
AVPR2 p.Arg137Cys Pathogenic ★★ same type
AVPR2 p.Arg137His Pathogenic ★★ same type
AVPR2 p.Arg202Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
AVPR2 p.Arg337Ter Pathogenic ★★ same type
AVPR2 p.Asp85Asn Pathogenic ★★ same type

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-arg181his (accessed [today's date]).

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