Is RORB p.Arg255Gly (c.763A>G) pathogenic?

RORB p.Arg255Gly (c.763A>G) is classified Uncertain significance in RORB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-22). AlphaMissense: likely benign (0.1972); Very rare (popmax 0.00133%, afr).

How common is RORB p.Arg255Gly (c.763A>G) in the general population?

RORB p.Arg255Gly (c.763A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about RORB p.Arg255Gly (c.763A>G)?

AlphaMissense predicts likely benign (score 0.1972) — an in-silico prediction, not a clinical call.

RORB p.Arg255Gly

c.763A>G · VCV3678908

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1972	likely benign
REVEL	0.787	moderately pathogenic-leaning
SaProt	LLR -7.33	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.56	acceptor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 8	GERP 0.095, phastCons 1
Regional constraint	o/e 0.34	constrained · MANE · 4,905 bp · p 1.1e-12 · regional, not allelic
Overall
CADD	24.7	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 R266G vs ClinVar R255G) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,044 alleles

Overall 0.000124% 2/1,613,994 alleles · very rare exomes 2/1,461,700 · genomes 0/152,294 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,044
European (non-Finnish)	8.48e-05%	1,179,915

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.Arg255Gly
Coding: c.763A>G
MANE Select: NM_006914
Type: single nucleotide variant
Location: chr9:74662477 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.48
Residue 266 UniProt numbering: the nr lbd domain; a UniProt-annotated variant site (in eig15; loss of subcellular location in the nucleoplasm)

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

Similar variants

RORB c.94-1G>A Pathogenic/Likely pathogenic ★★ same type
RORB p.Arg214Ter Pathogenic/Likely pathogenic ★★ same type
RORB p.Arg372Ter Pathogenic ★★ same type
RORB p.Arg66Ter Pathogenic/Likely pathogenic ★★ same type
RORB p.Ala269Thr Uncertain significance ★★ ⚠ same type
RORB p.Ala95Thr Uncertain significance ★★ ⚠ same type
RORB p.Arg214Gln Uncertain significance ★★ ⚠ same type
RORB p.Arg279Trp 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/rorb-p-arg255gly (accessed [today's date]).

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