Is NR0B2 p.Pro46= (c.138C>T) pathogenic?

NR0B2 p.Pro46= (c.138C>T) is classified Likely benign in NR0B2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-04). Very rare (popmax 0.00361%, nfe).

How common is NR0B2 p.Pro46= (c.138C>T) in the general population?

NR0B2 p.Pro46= (c.138C>T) is very rare (popmax 0.00361%, nfe) (gnomAD).

NR0B2 p.Pro46=

c.138C>T · rs370821222 · VCV1587422

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00361%, nfe)

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 -6.4	GERP -4.1
Overall
CADD	1.109	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00361% European (non-Finnish) · 41/1,136,372 alleles

Filtering AF 0.00268% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00295% 45/1,527,262 alleles · very rare exomes 39/1,375,076 · genomes 6/152,186 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00511%	19,561
European (non-Finnish)grpmax	0.00361%	27,716
Admixed American	0.0021%	47,526

Remaining individuals 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: NR0B2
Protein: p.Pro46=
Coding: c.138C>T
MANE Select: NM_021969
dbSNP: rs370821222
Type: single nucleotide variant
Location: chr1:26913803 (GRCh38)
Gene constraint: LOEUF 1.34 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.42 · 14 PDB
Residue 46: the nr lbd domain

Full NR0B2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NR0B2 p.Ala145Val Uncertain significance ★★ ⚠ same type
NR0B2 p.Arg238Cys Uncertain significance ★★ ⚠ same type
NR0B2 p.Arg54Cys Uncertain significance ★★ ⚠ same type
NR0B2 p.Arg71Gly Uncertain significance ★★ ⚠ same type
NR0B2 p.Arg86Trp Uncertain significance ★★ ⚠ same type
NR0B2 p.Asp245Gly Uncertain significance ★★ ⚠ same type
NR0B2 p.Gln84Glu Uncertain significance ★★ ⚠ same type
NR0B2 p.Leu118Val Uncertain significance ★★ ⚠ 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/nr0b2-p-pro46 (accessed [today's date]).

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