Is RORB p.Ala249Val (c.746C>T) pathogenic?

RORB p.Ala249Val (c.746C>T) is classified Conflicting classifications of pathogenicity in RORB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-02-13). AlphaMissense: likely benign (0.0596); Very rare (popmax 0.000509%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RORB p.Ala249Val (c.746C>T)?

RORB p.Ala249Val (c.746C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RORB p.Ala249Val (c.746C>T) in the general population?

RORB p.Ala249Val (c.746C>T) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about RORB p.Ala249Val (c.746C>T)?

AlphaMissense predicts likely benign (score 0.0596) — an in-silico prediction, not a clinical call.

RORB p.Ala249Val

c.746C>T · rs767017783 · VCV2269374

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0596 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0596	likely benign
REVEL	0.297	indeterminate
SaProt	LLR -7.09	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 2, phastCons 0.56
Regional constraint	o/e 0.34	constrained · MANE · 4,905 bp · p 1.1e-12 · regional, not allelic
Overall
CADD	15.75	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 A260V vs ClinVar A249V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000509% European (non-Finnish) · 6/1,179,396 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,612,034 alleles · very rare exomes 6/1,459,734 · genomes 0/152,300 · joint denominator

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.Ala249Val
Coding: c.746C>T
MANE Select: NM_006914
dbSNP: rs767017783
Type: single nucleotide variant
Location: chr9:74660725 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.48
Residue 260 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

Disease context

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

Similar variants

RORB p.Ala95Thr Uncertain significance ★★ ⚠ same condition
RORB p.Arg214Gln Uncertain significance ★★ ⚠ same condition
RORB p.Asp337Glu Uncertain significance ★★ ⚠ same condition
RORB p.Gln107Arg Uncertain significance ★★ ⚠ same condition
RORB p.Ile147Thr Uncertain significance ★★ ⚠ same condition
RORB p.Ile183Val Uncertain significance ★★ ⚠ same condition
RORB p.Pro205Ser Likely benign ★★ same condition
RORB p.Cys10Ter 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-ala249val (accessed [today's date]).

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