Is RORA p.Glu486Gln (c.1456G>C) pathogenic?

RORA p.Glu486Gln (c.1456G>C) is classified Likely benign in RORA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: ambiguous (0.4026); Rare (popmax 0.133%, amr).

How common is RORA p.Glu486Gln (c.1456G>C) in the general population?

RORA p.Glu486Gln (c.1456G>C) is rare (popmax 0.133%, amr) (gnomAD).

What do computational predictors say about RORA p.Glu486Gln (c.1456G>C)?

AlphaMissense predicts ambiguous (score 0.4026) — an in-silico prediction, not a clinical call.

RORA p.Glu486Gln

c.1456G>C · VCV3778009

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4026 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.133%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4026	ambiguous
REVEL	0.726	pathogenic-leaning
SaProt	LLR -9.53	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 5, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 14 kb · p 1.2e-11 · regional, not allelic
Overall
CADD	27.3	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 0.133% Admixed American · 80/59,992 alleles

Filtering AF 0.11% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.00527% 85/1,612,716 alleles · rare exomes 74/1,460,552 · genomes 11/152,164 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.133%	750
Remaining individualsnot grpmax-eligible	0.0032%	31,221
European (non-Finnish)	0.000254%	392,943

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.Glu486Gln
Coding: c.1456G>C
MANE Select: NM_134261
Type: single nucleotide variant
Location: chr15:60497571 (GRCh38)
Gene constraint: LOEUF 0.207 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.40 · 3 PDB
Residue 486: the nr lbd domain; an α-helix

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

Similar variants

RORA p.Arg462Ter Pathogenic/Likely pathogenic ★★ same type
RORA p.Arg500Ter Pathogenic/Likely pathogenic ★★ same type
RORA p.Ala11Val Uncertain significance ★★ ⚠ same type
RORA p.Ala358Thr Uncertain significance ★★ same type
RORA p.Ala7Ser Uncertain significance ★★ ⚠ same type
RORA p.Arg170His Uncertain significance ★★ ⚠ same type
RORA p.Arg462Gln Uncertain significance ★★ ⚠ same type
RORA p.Arg47Thr Uncertain significance ★★ same type

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-glu486gln (accessed [today's date]).

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