Is AQP4 p.Pro67= (c.201G>T) pathogenic?

AQP4 p.Pro67= (c.201G>T) is classified Benign in AQP4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-18). Common (popmax 12.5%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with AQP4-related disorder.

What condition is associated with AQP4 p.Pro67= (c.201G>T)?

AQP4 p.Pro67= (c.201G>T) is associated with AQP4-related disorder (ClinVar).

AQP4 p.Pro67=

Q: How common is AQP4 p.Pro67= (c.201G>T) in the general population?

AQP4 p.Pro67= (c.201G>T) is common (popmax 12.5%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.201G>T · rs35248760 · VCV3060164

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 12.5%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

AQP4-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -4.2
Overall
CADD	0.036	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.5% European (non-Finnish) · 147,439/1,179,994 alleles

Filtering AF 12.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.4%

Overall 10.9% 176,506/1,614,072 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	15.8%	6
Finnishnot grpmax-eligible	14.8%	7
European (non-Finnish)grpmax	12.5%	8
Ashkenazi Jewishnot grpmax-eligible	12.5%	8
Remaining individualsnot grpmax-eligible	10.5%	10
Middle Eastern	8.09%	12
Admixed American	7.48%	13
South Asian	2.94%	34
African / African-American	2.02%	49
East Asian	0.0201%	4,987

Amish 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: AQP4
Protein: p.Pro67=
Coding: c.201G>T
MANE Select: NM_001650
dbSNP: rs35248760
Type: single nucleotide variant
Location: chr18:26862428 (GRCh38)
Gene constraint: LOEUF 0.903 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.50 · 4 PDB
Residue 67: an α-helix

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

Disease context

AQP4-related disorder

Similar variants

AQP4 p.Arg19Thr Likely benign same condition
AQP4 p.Ile128Thr Likely benign same condition
AQP4 p.Thr289Met Likely benign same condition
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

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-pro67 (accessed [today's date]).

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