RORA p.Thr476=

Q: Is RORA p.Thr476= (c.1428C>A) pathogenic?

RORA p.Thr476= (c.1428C>A) is classified Benign in RORA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-11-07). Common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele; Associated with intellectual developmental disorder with or without epilepsy or cerebellar ataxia.

Q: What condition is associated with RORA p.Thr476= (c.1428C>A)?

RORA p.Thr476= (c.1428C>A) is associated with intellectual developmental disorder with or without epilepsy or cerebellar ataxia (ClinVar).

Q: How common is RORA p.Thr476= (c.1428C>A) in the general population?

RORA p.Thr476= (c.1428C>A) is common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1428C>A · rs11071539 · VCV1327966

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

intellectual developmental disorder with or without epilepsy or cerebellar ataxia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -5.7, phastCons 0.001
Overall
CADD	1.414	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 100% East Asian · 44,875/44,876 alleles

Filtering AF 99.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.7%

Overall 98.9% 1,595,323/1,612,332 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	100%	1
Amishnot grpmax-eligible	100%	1
East Asiangrpmax	100%	1
Finnishnot grpmax-eligible	100%	1
European (non-Finnish)	99.9%	1
Middle Eastern	98.9%	1
Admixed American	98.8%	1
Remaining individualsnot grpmax-eligible	98.7%	1
South Asian	98.6%	1
African / African-American	82.9%	1

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr476=
Coding: c.1428C>A
MANE Select: NM_134261
dbSNP: rs11071539
Type: single nucleotide variant
Location: chr15:60497599 (GRCh38)
Gene constraint: LOEUF 0.207 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.40 · 3 PDB
Residue 476: the nr lbd domain; a UniProt-annotated variant site (no effect on cerebellar development, when assayed in a heterologous system); 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.Thr476Ala 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-thr476 (accessed [today's date]).

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