Is AVPR1B p.Arg375His (c.1124G>A) pathogenic?

AVPR1B p.Arg375His (c.1124G>A) is classified Uncertain significance in AVPR1B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-22). AlphaMissense: likely benign (0.0813); Ultra-rare (popmax 0.0151%, amr).

How common is AVPR1B p.Arg375His (c.1124G>A) in the general population?

AVPR1B p.Arg375His (c.1124G>A) is ultra-rare (popmax 0.0151%, amr) (gnomAD).

What do computational predictors say about AVPR1B p.Arg375His (c.1124G>A)?

AlphaMissense predicts likely benign (score 0.0813) — an in-silico prediction, not a clinical call.

AVPR1B p.Arg375His

c.1124G>A · rs200584574 · VCV2406927

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0813 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0151%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.0813	likely benign
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 1, phastCons 0.99
Regional constraint	o/e 1.07	unconstrained · MANE · 6,698 bp · p 0.11 · regional, not allelic
Overall
CADD	24.2	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 0.0151% Admixed American · 9/59,686 alleles

Filtering AF 0.00777% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00581%

Overall 0.00255% 41/1,610,980 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0151%	6,632
South Asian	0.0077%	12,982
African / African-American	0.00667%	15,002
Remaining individualsnot grpmax-eligible	0.00482%	20,761
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,506
European (non-Finnish)	0.00136%	73,696

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: AVPR1B
Protein: p.Arg375His
Coding: c.1124G>A
MANE Select: NM_000707
dbSNP: rs200584574
Type: single nucleotide variant
Location: chr1:206110340 (GRCh38)
Gene constraint: LOEUF 1.194 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.18

Full AVPR1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AVPR1B p.Arg375Cys Uncertain significance ★ ⚠ same residue
AVPR1B p.Leu113Val Uncertain significance ★★ ⚠ same type
AVPR1B p.Thr129= Likely benign ★★ same type
AVPR1B p.Trp187Arg Likely benign ★★ same type
AVPR1B p.Ala319Thr Uncertain significance ★ ⚠ same type
AVPR1B p.Ala34Thr Uncertain significance ★ ⚠ same type
AVPR1B p.Arg132Cys Uncertain significance ★ ⚠ same type
AVPR1B p.Arg141His Uncertain significance ★ ⚠ 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/avpr1b-p-arg375his (accessed [today's date]).

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