Is RORA p.Glu417Asp (c.1251A>C) pathogenic?

RORA p.Glu417Asp (c.1251A>C) is classified Uncertain significance in RORA (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-08). AlphaMissense: ambiguous (0.3533); Very rare (popmax 8.5e-05%, nfe); Associated with intellectual developmental disorder with or without epilepsy or cerebellar ataxia.

How common is RORA p.Glu417Asp (c.1251A>C) in the general population?

RORA p.Glu417Asp (c.1251A>C) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about RORA p.Glu417Asp (c.1251A>C)?

AlphaMissense predicts ambiguous (score 0.3533) — an in-silico prediction, not a clinical call.

RORA p.Glu417Asp

Q: What condition is associated with RORA p.Glu417Asp (c.1251A>C)?

RORA p.Glu417Asp (c.1251A>C) is associated with intellectual developmental disorder with or without epilepsy or cerebellar ataxia (ClinVar).

c.1251A>C · rs2541974560 · VCV2442153

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3533 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Conditions

intellectual developmental disorder with or without epilepsy or cerebellar ataxia

Computational evidence

Protein change
AlphaMissense	0.3533	ambiguous
REVEL	0.456	indeterminate
SaProt	LLR -5.32	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 2.7, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 14 kb · p 1.2e-11 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.5e-05% European (non-Finnish) · 1/1,176,652 alleles

Overall 6.86e-05% 1/1,457,768 alleles · very rare

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.Glu417Asp
Coding: c.1251A>C
MANE Select: NM_134261
dbSNP: rs2541974560
Type: single nucleotide variant
Location: chr15:60501002 (GRCh38)
Gene constraint: LOEUF 0.207 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.40 · 3 PDB
Residue 417: the nr lbd domain; an α-helix

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.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
RORA p.Val268Met 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-glu417asp (accessed [today's date]).

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