Is RORB p.Cys65Ser (c.193T>A) pathogenic?

RORB p.Cys65Ser (c.193T>A) is classified Likely pathogenic in RORB (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-06). AlphaMissense: likely pathogenic (1); Absent from gnomAD v4.1; Associated with epilepsy, idiopathic generalized, susceptibility to, 15.

What condition is associated with RORB p.Cys65Ser (c.193T>A)?

RORB p.Cys65Ser (c.193T>A) is associated with epilepsy, idiopathic generalized, susceptibility to, 15 (ClinVar).

How common is RORB p.Cys65Ser (c.193T>A) in the general population?

RORB p.Cys65Ser (c.193T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RORB p.Cys65Ser (c.193T>A)?

AlphaMissense predicts likely pathogenic (score 1) — an in-silico prediction, not a clinical call.

RORB p.Cys65Ser

c.193T>A · rs2489566956 · VCV1709380

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

1 · 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	1	likely pathogenic ✓ concordant with ClinVar · top 9% in RORB
REVEL	0.969	strongly pathogenic-leaning
SaProt	LLR -15.73	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 7.9	GERP 2.9, phastCons 1
Regional constraint	o/e 0.32	constrained · MANE · 144 kb · p 1.9e-13 · regional, not allelic
Overall
CADD	29.3	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 C76S vs ClinVar C65S) — 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.Cys65Ser
Coding: c.193T>A
MANE Select: NM_006914
dbSNP: rs2489566956
Type: single nucleotide variant
Location: chr9:74634730 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.48
Residue 76 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 p.Cys65Ter Likely pathogenic ★ same residue
RORB p.Cys65Trp Uncertain significance ★ ⚠ same residue
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

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-cys65ser (accessed [today's date]).

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