Is RORB p.Cys46Phe (c.137G>T) pathogenic?

RORB p.Cys46Phe (c.137G>T) is classified Conflicting classifications of pathogenicity in RORB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-05-04). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1; Associated with epilepsy, idiopathic generalized, susceptibility to, 15.

What condition is associated with RORB p.Cys46Phe (c.137G>T)?

RORB p.Cys46Phe (c.137G>T) is associated with epilepsy, idiopathic generalized, susceptibility to, 15 (ClinVar).

How common is RORB p.Cys46Phe (c.137G>T) in the general population?

RORB p.Cys46Phe (c.137G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RORB p.Cys46Phe (c.137G>T)?

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

RORB p.Cys46Phe

c.137G>T · rs2118433165 · VCV1353211

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

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

epilepsy, idiopathic generalized, susceptibility to, 15

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic · top 9% in RORB
REVEL	0.959	strongly pathogenic-leaning
SaProt	LLR -14.01	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 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.32	constrained · MANE · 144 kb · p 1.9e-13 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM C57F vs ClinVar C46F) — verify the residue.

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: RORB
Protein: p.Cys46Phe
Coding: c.137G>T
MANE Select: NM_006914
dbSNP: rs2118433165
Type: single nucleotide variant
Location: chr9:74634674 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.48
Residue 57 UniProt numbering: a DNA-binding region

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

Disease context

epilepsy, idiopathic generalized, susceptibility to, 15 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RORB c.94-1G>A Pathogenic/Likely pathogenic ★★ same condition
RORB p.Arg66Ter Pathogenic/Likely pathogenic ★★ same condition
RORB p.Phe33Leu Uncertain significance ★★ ⚠ same condition
RORB c.1225-9G>A Likely benign ★★ same condition
RORB p.Ile25= Benign/Likely benign ★★ same condition
RORB p.Leu118= Benign/Likely benign ★★ same condition
RORB c.1224+1G>T Likely pathogenic ★ same condition
RORB c.8-1G>A 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/rorb-p-cys46phe (accessed [today's date]).

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