Is NR4A2 p.Ser366Arg (c.1098T>G) pathogenic?

NR4A2 p.Ser366Arg (c.1098T>G) is classified Uncertain significance in NR4A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-03). AlphaMissense: likely pathogenic (0.9831); Absent from gnomAD v4.1.

How common is NR4A2 p.Ser366Arg (c.1098T>G) in the general population?

NR4A2 p.Ser366Arg (c.1098T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NR4A2 p.Ser366Arg (c.1098T>G)?

AlphaMissense predicts likely pathogenic (score 0.9831) — an in-silico prediction, not a clinical call.

NR4A2 p.Ser366Arg

c.1098T>G · VCV3367407

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9831 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9831	likely pathogenic
REVEL	0.184	benign-leaning
SaProt	LLR -10.63	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP -1, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 2,216 bp · p 0.00051 · regional, not allelic
Overall
CADD	24.0	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

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: NR4A2
Protein: p.Ser366Arg
Coding: c.1098T>G
MANE Select: NM_006186
Type: single nucleotide variant
Location: chr2:156327911 (GRCh38)
Gene constraint: LOEUF 0.093 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.39 · 8 PDB
Residue 366: the nr lbd domain; an α-helix

Full NR4A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NR4A2 p.Ser366Gly Likely benign ★ same residue
NR4A2 p.Arg370Lys Uncertain significance ★★ ⚠ same type
NR4A2 p.Leu300Ser Uncertain significance ★★ ⚠ same type
NR4A2 p.Phe287Leu Uncertain significance ★★ ⚠ same type
NR4A2 p.Pro124= Uncertain significance ★★ same type
NR4A2 c.-223C>T Likely benign ★★ same type
NR4A2 c.*331T>G Benign ★★ same type
NR4A2 p.Ile163= Benign/Likely benign ★★ 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/nr4a2-p-ser366arg (accessed [today's date]).

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