Is NR4A2 p.Pro124= (c.372C>T) pathogenic?

NR4A2 p.Pro124= (c.372C>T) is classified Uncertain significance in NR4A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-01-13). Very rare (popmax 0.0011%, sas); Associated with late-onset Parkinson disease.

What condition is associated with NR4A2 p.Pro124= (c.372C>T)?

NR4A2 p.Pro124= (c.372C>T) is associated with late-onset Parkinson disease (ClinVar).

How common is NR4A2 p.Pro124= (c.372C>T) in the general population?

NR4A2 p.Pro124= (c.372C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Hereditary late-onset Parkinson disease inherited?

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

NR4A2 p.Pro124=

c.372C>T · rs943205037 · VCV894759

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

late-onset Parkinson disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP -0.51, phastCons 1
Overall
CADD	12.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,086 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,613,802 alleles · very rare exomes 5/1,461,648 · genomes 1/152,154 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,086
European (non-Finnish)	0.000424%	235,969

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: NR4A2
Protein: p.Pro124=
Coding: c.372C>T
MANE Select: NM_006186
dbSNP: rs943205037
Type: single nucleotide variant
Location: chr2:156329815 (GRCh38)
Gene constraint: LOEUF 0.093 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.39 · 8 PDB

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

Disease context

late-onset Parkinson disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary late-onset Parkinson disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

NR4A2 c.-223C>T Likely benign ★★ same condition
NR4A2 c.*331T>G Benign ★★ same condition
NR4A2 p.Leu244= Benign/Likely benign ★★ same condition
NR4A2 p.Cys299Phe Pathogenic ★ same condition
NR4A2 c.1158+13C>T Uncertain significance ★ same condition
NR4A2 c.-144G>A Uncertain significance ★ same condition
NR4A2 c.-166C>G Uncertain significance ★ same condition
NR4A2 c.-227C>G Uncertain significance ★ 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/nr4a2-p-pro124 (accessed [today's date]).

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