Is RORB p.Ile25= (c.75C>T) pathogenic?

RORB p.Ile25= (c.75C>T) is classified Benign/Likely benign in RORB (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-04-01). Rare (popmax 0.502%, nfe); Associated with epilepsy, idiopathic generalized, susceptibility to, 15.

What condition is associated with RORB p.Ile25= (c.75C>T)?

RORB p.Ile25= (c.75C>T) is associated with epilepsy, idiopathic generalized, susceptibility to, 15 (ClinVar).

How common is RORB p.Ile25= (c.75C>T) in the general population?

RORB p.Ile25= (c.75C>T) is rare (popmax 0.502%, nfe) (gnomAD).

RORB p.Ile25=

c.75C>T · rs41307459 · VCV782753

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.502%, nfe)

Conditions

epilepsy, idiopathic generalized, susceptibility to, 15

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	GERP 2.2, phastCons 1
Overall
CADD	13.97	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.502% European (non-Finnish) · 5,919/1,179,138 alleles

Filtering AF 0.491% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.487%

Overall 0.49% 7,909/1,612,784 alleles · rare exomes 7,198/1,460,494 · genomes 711/152,290 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.88%	53
European (non-Finnish)grpmax	0.502%	199
Remaining individualsnot grpmax-eligible	0.45%	222
Admixed American	0.38%	263
Ashkenazi Jewishnot grpmax-eligible	0.325%	308
Middle Eastern	0.313%	319
South Asian	0.109%	918
African / African-American	0.0867%	1,154

Finnish 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: RORB
Protein: p.Ile25=
Coding: c.75C>T
MANE Select: NM_006914
dbSNP: rs41307459
Type: single nucleotide variant
Location: chr9:74630349 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.48
Residue 25: 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.Leu118= Benign/Likely benign ★★ same condition
RORB c.1224+1G>T Likely pathogenic ★ same condition
RORB c.8-1G>A Likely pathogenic ★ same condition
RORB p.Cys65Ser 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-ile25 (accessed [today's date]).

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