Is NR2E3 p.Pro399Gln (c.1196C>A) pathogenic?

NR2E3 p.Pro399Gln (c.1196C>A) is classified Uncertain significance in NR2E3 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-11-08). AlphaMissense: likely pathogenic (0.666); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with NR2E3 p.Pro399Gln (c.1196C>A)?

NR2E3 p.Pro399Gln (c.1196C>A) is associated with Inborn genetic diseases, enhanced S-cone syndrome (ClinVar).

How common is NR2E3 p.Pro399Gln (c.1196C>A) in the general population?

NR2E3 p.Pro399Gln (c.1196C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NR2E3 p.Pro399Gln (c.1196C>A)?

AlphaMissense predicts likely pathogenic (score 0.666) — an in-silico prediction, not a clinical call.

NR2E3 p.Pro399Gln

c.1196C>A · rs1049248530 · VCV3201922

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.666 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.666	likely pathogenic
REVEL	0.631	indeterminate
SaProt	LLR -14.27	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 6,937 bp · p 0.89 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NR2E3
Protein: p.Pro399Gln
Coding: c.1196C>A
MANE Select: NM_014249
dbSNP: rs1049248530
Type: single nucleotide variant
Location: chr15:71817647 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: enhanced S-cone syndrome

Similar variants

NR2E3 p.Pro399Thr Conflicting classifications of pathogenicity ★ same residue
NR2E3 p.Pro399Ala Uncertain significance ★ ⚠ same residue
NR2E3 p.Pro399Leu Uncertain significance ★ ⚠ same residue
NR2E3 c.118+1G>T Likely pathogenic ★★ same condition
NR2E3 c.119-2A>C Pathogenic/Likely pathogenic ★★ same condition
NR2E3 c.119-2A>G Pathogenic ★★ same condition
NR2E3 c.119-2A>T Pathogenic/Likely pathogenic ★★ same condition
NR2E3 c.349+5G>C Pathogenic/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/nr2e3-p-pro399gln (accessed [today's date]).

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