Is AVPR1B p.Arg375Cys (c.1123C>T) pathogenic?

AVPR1B p.Arg375Cys (c.1123C>T) is classified Uncertain significance in AVPR1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely benign (0.0931); Very rare (popmax 0.00568%, nfe).

How common is AVPR1B p.Arg375Cys (c.1123C>T) in the general population?

AVPR1B p.Arg375Cys (c.1123C>T) is very rare (popmax 0.00568%, nfe) (gnomAD).

What do computational predictors say about AVPR1B p.Arg375Cys (c.1123C>T)?

AlphaMissense predicts likely benign (score 0.0931) — an in-silico prediction, not a clinical call.

AVPR1B p.Arg375Cys

c.1123C>T · rs372765655 · VCV3132432

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0931 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00568%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.0931	likely benign
SaProt	LLR -7.54	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 8.5	GERP 0.95, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 6,698 bp · p 0.11 · regional, not allelic
Overall
CADD	27.6	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 0.00568% European (non-Finnish) · 67/1,178,842 alleles

Filtering AF 0.00454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00417%

Overall 0.022% 354/1,610,032 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.824%	121
Remaining individualsnot grpmax-eligible	0.0563%	1,777
European (non-Finnish)grpmax	0.00568%	17,595
Admixed American	0.00504%	19,841
South Asian	0.00441%	22,700
African / African-American	0.00267%	37,444

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg375Cys
Coding: c.1123C>T
MANE Select: NM_000707
dbSNP: rs372765655
Type: single nucleotide variant
Location: chr1:206110341 (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.Arg375His 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-arg375cys (accessed [today's date]).

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