Is RORA p.Ala330Val (c.989C>T) pathogenic?

RORA p.Ala330Val (c.989C>T) is classified Uncertain significance in RORA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-22). AlphaMissense: likely pathogenic (0.9621); Absent from gnomAD v4.1; Associated with intellectual developmental disorder with or without epilepsy or cerebellar ataxia.

How common is RORA p.Ala330Val (c.989C>T) in the general population?

RORA p.Ala330Val (c.989C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RORA p.Ala330Val (c.989C>T)?

AlphaMissense predicts likely pathogenic (score 0.9621) — an in-silico prediction, not a clinical call.

RORA p.Ala330Val

Q: What condition is associated with RORA p.Ala330Val (c.989C>T)?

RORA p.Ala330Val (c.989C>T) is associated with intellectual developmental disorder with or without epilepsy or cerebellar ataxia (ClinVar).

c.989C>T · VCV4079883

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9621 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with or without epilepsy or cerebellar ataxia

Computational evidence

Protein change
AlphaMissense	0.9621	likely pathogenic
REVEL	0.767	pathogenic-leaning
SaProt	LLR -10.84	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 12	GERP 7.2, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 14 kb · p 1.2e-11 · regional, not allelic
Overall
CADD	32.0	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RORA
Protein: p.Ala330Val
Coding: c.989C>T
MANE Select: NM_134261
Type: single nucleotide variant
Location: chr15:60503621 (GRCh38)
Gene constraint: LOEUF 0.207 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.40 · 3 PDB
Residue 330: 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-ala330val (accessed [today's date]).

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