Is RORB p.Ala269Pro (c.805G>C) pathogenic?

RORB p.Ala269Pro (c.805G>C) is classified Uncertain significance in RORB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-22). AlphaMissense: likely pathogenic (0.9978); Absent from gnomAD v4.1.

How common is RORB p.Ala269Pro (c.805G>C) in the general population?

RORB p.Ala269Pro (c.805G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RORB p.Ala269Pro (c.805G>C)?

AlphaMissense predicts likely pathogenic (score 0.9978) — an in-silico prediction, not a clinical call.

RORB p.Ala269Pro

c.805G>C · VCV3642454

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9978 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9978	likely pathogenic
REVEL	0.955	strongly pathogenic-leaning
SaProt	LLR -12.88	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 2.7, phastCons 1
Regional constraint	o/e 0.34	constrained · MANE · 4,905 bp · p 1.1e-12 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A280P vs ClinVar A269P) — 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.Ala269Pro
Coding: c.805G>C
MANE Select: NM_006914
Type: single nucleotide variant
Location: chr9:74662519 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.48
Residue 280 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 p.Ala269Thr Uncertain significance ★★ ⚠ same residue
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.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-ala269pro (accessed [today's date]).

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