Is NR2E3 p.Pro399Ala (c.1195C>G) pathogenic?

NR2E3 p.Pro399Ala (c.1195C>G) is classified Uncertain significance in NR2E3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-25). AlphaMissense: likely benign (0.2947); Ultra-rare (popmax 0.0165%, mid).

How common is NR2E3 p.Pro399Ala (c.1195C>G) in the general population?

NR2E3 p.Pro399Ala (c.1195C>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about NR2E3 p.Pro399Ala (c.1195C>G)?

AlphaMissense predicts likely benign (score 0.2947) — an in-silico prediction, not a clinical call.

NR2E3 p.Pro399Ala

c.1195C>G · rs199564404 · VCV1345603

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2947 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2947	likely benign
REVEL	0.706	pathogenic-leaning
SaProt	LLR -12.74	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
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	24.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,050 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000275% 4/1,455,520 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,050
East Asian	0.00224%	44,652
European (non-Finnish)	0.00017%	587,354

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.Pro399Ala
Coding: c.1195C>G
MANE Select: NM_014249
dbSNP: rs199564404
Type: single nucleotide variant
Location: chr15:71817646 (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

Similar variants

NR2E3 p.Pro399Gln Uncertain significance ★ ⚠ same residue
NR2E3 p.Pro399Leu Uncertain significance ★ ⚠ same residue
NR2E3 p.Pro399Thr Conflicting classifications of pathogenicity ★ same residue
NR2E3 p.Pro399fs Likely pathogenic ★ same residue
NR2E3 c.118+1G>T Likely pathogenic ★★ same type
NR2E3 c.119-2A>C Pathogenic/Likely pathogenic ★★ same type
NR2E3 c.119-2A>G Pathogenic ★★ same type
NR2E3 c.119-2A>T 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-pro399ala (accessed [today's date]).

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