Is RORB p.Arg66Gln (c.197G>A) pathogenic?

RORB p.Arg66Gln (c.197G>A) is classified Conflicting classifications of pathogenicity in RORB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-04-28). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with RORB p.Arg66Gln (c.197G>A)?

RORB p.Arg66Gln (c.197G>A) is associated with Inborn genetic diseases (ClinVar).

How common is RORB p.Arg66Gln (c.197G>A) in the general population?

RORB p.Arg66Gln (c.197G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RORB p.Arg66Gln (c.197G>A)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

RORB p.Arg66Gln

c.197G>A · rs756765022 · VCV1370911

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 9% in RORB
REVEL	0.944	strongly pathogenic-leaning
SaProt	LLR -14.15	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	34.0	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 R77Q vs ClinVar R66Q) — 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.Arg66Gln
Coding: c.197G>A
MANE Select: NM_006914
dbSNP: rs756765022
Type: single nucleotide variant
Location: chr9:74634734 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.48
Residue 77 UniProt numbering: a DNA-binding region; 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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RORB p.Arg66Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
RORB p.Arg66Ter Pathogenic/Likely pathogenic ★★ same residue
RORB p.Arg66Pro Uncertain significance ★★ ⚠ same residue
RORB p.Arg66Leu Uncertain significance ★ ⚠ same residue
RORB p.Arg66= Likely benign ★ same residue
RORB p.Ala95Thr Uncertain significance ★★ ⚠ same condition
RORB p.Arg214Gln Uncertain significance ★★ ⚠ same condition
RORB p.Asp337Glu Uncertain significance ★★ ⚠ 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-arg66gln (accessed [today's date]).

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