Is NR2F1 p.Arg135Pro (c.404G>C) pathogenic?

NR2F1 p.Arg135Pro (c.404G>C) is classified Pathogenic in NR2F1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-01). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1; Associated with Bosch-Boonstra-Schaaf optic atrophy syndrome.

What condition is associated with NR2F1 p.Arg135Pro (c.404G>C)?

NR2F1 p.Arg135Pro (c.404G>C) is associated with Bosch-Boonstra-Schaaf optic atrophy syndrome (ClinVar).

How common is NR2F1 p.Arg135Pro (c.404G>C) in the general population?

NR2F1 p.Arg135Pro (c.404G>C) is absent from gnomAD v4.1 (gnomAD).

How is Optic atrophy-intellectual disability syndrome inherited?

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

What do computational predictors say about NR2F1 p.Arg135Pro (c.404G>C)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

NR2F1 p.Arg135Pro

c.404G>C · VCV3897853

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bosch-Boonstra-Schaaf optic atrophy syndrome

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic ✓ concordant with ClinVar · top 10% in NR2F1
REVEL	0.976	strongly pathogenic-leaning
SaProt	LLR -14.49	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.14	constrained · MANE · 2,681 bp · p 7.2e-20 · regional, not allelic
Overall
CADD	35.0	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: NR2F1
Protein: p.Arg135Pro
Coding: c.404G>C
MANE Select: NM_005654
Type: single nucleotide variant
Location: chr5:93585427 (GRCh38)
Gene constraint: LOEUF 0.133 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 76.81 · 1 PDB
Residue 135: a β-strand; a DNA-binding region

Full NR2F1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Bosch-Boonstra-Schaaf optic atrophy syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Optic atrophy-intellectual disability syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Neonatal

Similar variants

NR2F1 p.Arg135His Likely pathogenic ★ same residue
NR2F1 p.Arg135Leu Likely pathogenic ★ same residue
NR2F1 c.463+1G>A Likely pathogenic ★★ same condition
NR2F1 p.Arg366Cys Likely pathogenic ★★ same condition
NR2F1 p.Cys128Arg Likely pathogenic ★★ same condition
NR2F1 p.Cys146Tyr Pathogenic/Likely pathogenic ★★ same condition
NR2F1 p.Cys86Arg Pathogenic/Likely pathogenic ★★ same condition
NR2F1 p.Gly105Ser 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/nr2f1-p-arg135pro (accessed [today's date]).

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