Is NR3C2 p.Pro699= (c.2097A>C) pathogenic?

NR3C2 p.Pro699= (c.2097A>C) is classified Benign in NR3C2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-01-13). Low-frequency (popmax 3.38%, afr); Associated with autosomal dominant pseudohypoaldosteronism type 1.

What condition is associated with NR3C2 p.Pro699= (c.2097A>C)?

NR3C2 p.Pro699= (c.2097A>C) is associated with autosomal dominant pseudohypoaldosteronism type 1 (ClinVar).

How common is NR3C2 p.Pro699= (c.2097A>C) in the general population?

NR3C2 p.Pro699= (c.2097A>C) is low-frequency (popmax 3.38%, afr) (gnomAD).

How is Pseudohypoaldosteronism type 1 inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

NR3C2 p.Pro699=

c.2097A>C · rs780645360 · VCV900747

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.38%, afr)

Conditions

autosomal dominant pseudohypoaldosteronism type 1

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 -15	GERP -3.3
Overall
CADD	1.005	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.38% African / African-American · 159/4,700 alleles

Filtering AF 2.95% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.79%

Overall 1.79% 2,451/136,724 alleles · low-frequency exomes 1,997/130,268 · genomes 454/6,456 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	21.4%	5
African / African-Americangrpmax	3.38%	30
Finnishnot grpmax-eligible	2.96%	34
Remaining individualsnot grpmax-eligible	2.06%	49
European (non-Finnish)	1.85%	54
South Asian	1.57%	64
East Asian	0.9%	111
Ashkenazi Jewishnot grpmax-eligible	0.852%	117
Admixed American	0.704%	142
Middle Eastern	0.339%	295

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: NR3C2
Protein: p.Pro699=
Coding: c.2097A>C
MANE Select: NM_000901
dbSNP: rs780645360
Type: single nucleotide variant
Location: chr4:148154819 (GRCh38)
Gene constraint: LOEUF 0.268 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.96 · 30 PDB
Residue 699: the 'hinge' region; the 'disordered' region

Full NR3C2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant pseudohypoaldosteronism type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Pseudohypoaldosteronism type 1 (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (United Kingdom)

Similar variants

NR3C2 p.Pro699fs Likely pathogenic same residue
NR3C2 c.2799+1G>A Pathogenic/Likely pathogenic ★★ same condition
NR3C2 p.Arg590Ter Pathogenic ★★ same condition
NR3C2 p.Arg651Ter Pathogenic ★★ same condition
NR3C2 p.Arg652Ter Pathogenic ★★ same condition
NR3C2 p.Arg732Ter Pathogenic ★★ same condition
NR3C2 p.Arg947Ter Pathogenic ★★ same condition
NR3C2 p.Gln125Ter Likely pathogenic ★★ same condition

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/nr3c2-p-pro699 (accessed [today's date]).

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