Is RORA p.Val45Met (c.133G>A) pathogenic?

RORA p.Val45Met (c.133G>A) is classified Uncertain significance in RORA (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.1602); Very rare (popmax 0.0028%, afr); Associated with intellectual developmental disorder with or without epilepsy or cerebellar ataxia.

How common is RORA p.Val45Met (c.133G>A) in the general population?

RORA p.Val45Met (c.133G>A) is very rare (popmax 0.0028%, afr) (gnomAD).

What do computational predictors say about RORA p.Val45Met (c.133G>A)?

AlphaMissense predicts likely benign (score 0.1602) — an in-silico prediction, not a clinical call.

RORA p.Val45Met

Q: What condition is associated with RORA p.Val45Met (c.133G>A)?

RORA p.Val45Met (c.133G>A) is associated with intellectual developmental disorder with or without epilepsy or cerebellar ataxia (ClinVar).

c.133G>A · rs1351395580 · VCV1878520

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1602 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with or without epilepsy or cerebellar ataxia

Computational evidence

Protein change
AlphaMissense	0.1602	likely benign
REVEL	0.283	benign-leaning
SaProt	LLR -8.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.46, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 551 kb · p 0.0056 · regional, not allelic
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0028% African / African-American · 2/71,304 alleles

Filtering AF 0.000465% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000174%

Overall 0.00026% 4/1,538,026 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0028%	35,652
Admixed American	0.00198%	50,434
Remaining individualsnot grpmax-eligible	0.00168%	59,490

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: RORA
Protein: p.Val45Met
Coding: c.133G>A
MANE Select: NM_134261
dbSNP: rs1351395580
Type: single nucleotide variant
Location: chr15:61229086 (GRCh38)
Gene constraint: LOEUF 0.207 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.40 · 3 PDB
Residue 45: the 'disordered' region

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

Disease context

intellectual developmental disorder with or without epilepsy or cerebellar ataxia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RORA p.Val45= Likely benign ★ same residue
RORA p.Ala11Val Uncertain significance ★★ ⚠ same condition
RORA p.Ala7Ser Uncertain significance ★★ ⚠ same condition
RORA p.Arg170His Uncertain significance ★★ ⚠ same condition
RORA p.Arg462Gln Uncertain significance ★★ ⚠ same condition
RORA p.Arg47Thr Uncertain significance ★★ same condition
RORA p.Glu14Lys Uncertain significance ★★ ⚠ same condition
RORA p.His197Gln 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/rora-p-val45met (accessed [today's date]).

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