Is NR2E3 p.Pro399Thr (c.1195C>A) pathogenic?

NR2E3 p.Pro399Thr (c.1195C>A) is classified Conflicting classifications of pathogenicity in NR2E3 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-28). AlphaMissense: ambiguous (0.5436); Ultra-rare (popmax 0.0165%, mid); Associated with retinitis pigmentosa 37.

What condition is associated with NR2E3 p.Pro399Thr (c.1195C>A)?

NR2E3 p.Pro399Thr (c.1195C>A) is associated with retinitis pigmentosa 37, inherited retinal dystrophy, enhanced S-cone syndrome (ClinVar).

How common is NR2E3 p.Pro399Thr (c.1195C>A) in the general population?

NR2E3 p.Pro399Thr (c.1195C>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Retinitis pigmentosa inherited?

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

What do computational predictors say about NR2E3 p.Pro399Thr (c.1195C>A)?

AlphaMissense predicts ambiguous (score 0.5436) — an in-silico prediction, not a clinical call.

NR2E3 p.Pro399Thr

c.1195C>A · rs199564404 · VCV552868

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.5436 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

retinitis pigmentosa 37

Computational evidence

Protein change
AlphaMissense	0.5436	ambiguous
REVEL	0.626	indeterminate
SaProt	LLR -13.75	damaging
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	24.8	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 · 1/6,072 alleles

Filtering AF 0.00838% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0078%

Overall 0.0118% 189/1,607,702 alleles · ultra-rare exomes 172/1,455,518 · genomes 17/152,184 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.088%	1,137
Finnishnot grpmax-eligible	0.0579%	1,728
Middle Easterngrpmax	0.0165%	6,072
European (non-Finnish)	0.00987%	10,127
Remaining individualsnot grpmax-eligible	0.00965%	10,364
East Asian	0.00224%	44,664
African / African-American	0.00134%	74,848
South Asian	0.0011%	90,878

Ashkenazi Jewish 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: NR2E3
Protein: p.Pro399Thr
Coding: c.1195C>A
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

Disease context

retinitis pigmentosa 37 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: inherited retinal dystrophy enhanced S-cone syndrome

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

NR2E3 p.Pro399Gln Uncertain significance ★ ⚠ 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-pro399thr (accessed [today's date]).

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