Is RORB p.Leu286Phe (c.856C>T) pathogenic?

RORB p.Leu286Phe (c.856C>T) is classified Uncertain significance in RORB (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-12). AlphaMissense: likely pathogenic (0.8783); Very rare (popmax 0.00333%, amr).

How common is RORB p.Leu286Phe (c.856C>T) in the general population?

RORB p.Leu286Phe (c.856C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about RORB p.Leu286Phe (c.856C>T)?

AlphaMissense predicts likely pathogenic (score 0.8783) — an in-silico prediction, not a clinical call.

RORB p.Leu286Phe

c.856C>T · rs1160695348 · VCV1399434

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8783 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8783	likely pathogenic
REVEL	0.892	moderately pathogenic-leaning
SaProt	LLR -11.44	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 4	GERP 0.89, phastCons 1
Regional constraint	o/e 0.34	constrained · MANE · 4,905 bp · p 1.1e-12 · regional, not allelic
Overall
CADD	26.4	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 L297F vs ClinVar L286F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,992 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000186% 3/1,613,872 alleles · very rare exomes 2/1,461,724 · genomes 1/152,148 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,996
European (non-Finnish)	8.47e-05%	1,179,986

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.Leu286Phe
Coding: c.856C>T
MANE Select: NM_006914
dbSNP: rs1160695348
Type: single nucleotide variant
Location: chr9:74662570 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.48
Residue 297 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-leu286phe (accessed [today's date]).

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