Is AQP4 p.Pro296Arg (c.887C>G) pathogenic?

AQP4 p.Pro296Arg (c.887C>G) is classified Uncertain significance in AQP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-26). AlphaMissense: likely benign (0.1847); Very rare (popmax 0.01%, amr).

How common is AQP4 p.Pro296Arg (c.887C>G) in the general population?

AQP4 p.Pro296Arg (c.887C>G) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about AQP4 p.Pro296Arg (c.887C>G)?

AlphaMissense predicts likely benign (score 0.1847) — an in-silico prediction, not a clinical call.

AQP4 p.Pro296Arg

c.887C>G · rs768757331 · VCV2215588

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1847 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1847	likely benign
REVEL	0.407	indeterminate
SaProt	LLR -7.41	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 9,475 bp · p 0.85 · regional, not allelic
Overall
CADD	25.6	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 0.01% Admixed American · 6/60,018 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000547% 8/1,461,884 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,003
European (non-Finnish)	0.000169%	590,009

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: AQP4
Protein: p.Pro296Arg
Coding: c.887C>G
MANE Select: NM_001650
dbSNP: rs768757331
Type: single nucleotide variant
Location: chr18:26856296 (GRCh38)
Gene constraint: LOEUF 0.903 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.50 · 4 PDB

Full AQP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AQP4 p.Asp184Glu Benign ★★ same type
AQP4 p.Ile193Thr Likely benign ★★ same type
AQP4 p.Thr273= Benign ★★ same type
AQP4 p.Ala156Ser Uncertain significance ★ ⚠ same type
AQP4 p.Ala265Val Uncertain significance ★ ⚠ same type
AQP4 p.Arg216Ter Uncertain significance ★ same type
AQP4 p.Arg260Cys Uncertain significance ★ ⚠ same type
AQP4 p.Arg306Trp 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/aqp4-p-pro296arg (accessed [today's date]).

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