Is NR2E3 p.Pro399fs (c.1194del) pathogenic?

NR2E3 p.Pro399fs (c.1194del) is classified Likely pathogenic in NR2E3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). Very rare (popmax 8.51e-05%, nfe); Associated with retinal disorder.

What condition is associated with NR2E3 p.Pro399fs (c.1194del)?

NR2E3 p.Pro399fs (c.1194del) is associated with retinal disorder (ClinVar).

How common is NR2E3 p.Pro399fs (c.1194del) in the general population?

NR2E3 p.Pro399fs (c.1194del) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

NR2E3 p.Pro399fs

c.1194del · VCV4526904

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Conditions

retinal disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (8 of 8) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.8	GERP 0.54, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.51e-05% European (non-Finnish) · 1/1,174,960 alleles

Overall 6.22e-05% 1/1,608,132 alleles · very rare exomes 1/1,455,816 · genomes 0/152,316 · joint denominator

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: NR2E3
Protein: p.Pro399fs
Coding: c.1194del
MANE Select: NM_014249
Type: Deletion
Location: chr15:71817645 (GRCh38)
Gene constraint: LOEUF 1.47 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.59 · 1 PDB
Residue 399: the nr lbd domain; an α-helix

Full NR2E3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

retinal disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NR2E3 p.Pro399Ala Uncertain significance ★ ⚠ same residue
NR2E3 p.Pro399Gln Uncertain significance ★ ⚠ same residue
NR2E3 p.Pro399Leu Uncertain significance ★ ⚠ same residue
NR2E3 p.Pro399Thr Conflicting classifications of pathogenicity ★ same residue
NR2E3 c.119-2A>C Pathogenic/Likely pathogenic ★★ same condition
NR2E3 p.Ala117Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
NR2E3 p.Ser55del Uncertain significance ★ same condition
NR2E3 c.1101delG Pathogenic/Likely pathogenic ★★ 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/nr2e3-p-pro399fs (accessed [today's date]).

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