Is NR2C2 p.Arg464Trp (c.1390C>T) pathogenic?

NR2C2 p.Arg464Trp (c.1390C>T) is classified Uncertain significance in NR2C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-24). AlphaMissense: likely pathogenic (0.7641); Very rare (popmax 0.00446%, eas).

How common is NR2C2 p.Arg464Trp (c.1390C>T) in the general population?

NR2C2 p.Arg464Trp (c.1390C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about NR2C2 p.Arg464Trp (c.1390C>T)?

AlphaMissense predicts likely pathogenic (score 0.7641) — an in-silico prediction, not a clinical call.

NR2C2 p.Arg464Trp

c.1390C>T · VCV3407643

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7641 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7641	likely pathogenic
REVEL	0.783	moderately pathogenic-leaning
SaProt	LLR -12.13	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.50 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.8	GERP 0.84, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 13 kb · p 5.1e-15 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,804 alleles

Filtering AF 0.00074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000372% 6/1,612,948 alleles · very rare exomes 4/1,460,732 · genomes 2/152,216 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,402
South Asian	0.0011%	90,842
European (non-Finnish)	0.000254%	393,193

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: NR2C2
Protein: p.Arg464Trp
Coding: c.1390C>T
MANE Select: NM_001291694
Type: single nucleotide variant
Location: chr3:15038017 (GRCh38)
Gene constraint: LOEUF 0.159 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.50 · 5 PDB
Residue 464: the nr lbd domain

Full NR2C2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NR2C2 p.Thr224= Benign ★★ same type
NR2C2 c.72+1G>C Uncertain significance ★ same type
NR2C2 p.Ala319Val Uncertain significance ★ ⚠ same type
NR2C2 p.Ala59Thr Uncertain significance ★ ⚠ same type
NR2C2 p.Ala74Thr Uncertain significance ★ ⚠ same type
NR2C2 p.Arg101His Uncertain significance ★ ⚠ same type
NR2C2 p.Arg22His Uncertain significance ★ ⚠ same type
NR2C2 p.Arg254Cys 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/nr2c2-p-arg464trp (accessed [today's date]).

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