Is RORA p.His461Gln (c.1383C>A) pathogenic?

RORA p.His461Gln (c.1383C>A) is classified Uncertain significance in RORA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-21). AlphaMissense: likely benign (0.1232); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with RORA p.His461Gln (c.1383C>A)?

RORA p.His461Gln (c.1383C>A) is associated with Inborn genetic diseases (ClinVar).

How common is RORA p.His461Gln (c.1383C>A) in the general population?

RORA p.His461Gln (c.1383C>A) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about RORA p.His461Gln (c.1383C>A)?

AlphaMissense predicts likely benign (score 0.1232) — an in-silico prediction, not a clinical call.

RORA p.His461Gln

c.1383C>A · VCV3315047

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1232 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1232	likely benign
REVEL	0.669	pathogenic-leaning
SaProt	LLR -5.24	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 14 kb · p 1.2e-11 · regional, not allelic
Overall
CADD	18.16	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 0.00134% African / African-American · 1/74,678 alleles

Overall 0.000124% 2/1,609,346 alleles · very rare exomes 2/1,457,224 · genomes 0/152,122 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,678
European (non-Finnish)	8.5e-05%	1,177,072

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.His461Gln
Coding: c.1383C>A
MANE Select: NM_134261
Type: single nucleotide variant
Location: chr15:60499916 (GRCh38)
Gene constraint: LOEUF 0.207 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.40 · 3 PDB
Residue 461: the nr lbd domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RORA p.His461Arg Uncertain significance ★ ⚠ same residue
RORA p.Arg462Ter Pathogenic/Likely pathogenic ★★ same condition
RORA p.Ala7Ser Uncertain significance ★★ ⚠ same condition
RORA p.Gln278His Uncertain significance ★★ ⚠ same condition
RORA p.Gly211Arg Uncertain significance ★★ ⚠ same condition
RORA p.Lys151Gln Uncertain significance ★★ ⚠ same condition
RORA p.Thr328Arg Uncertain significance ★★ ⚠ same condition
RORA c.197-26379G>A Likely benign ★★ 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-his461gln (accessed [today's date]).

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