Is RORA p.Arg370His (c.1109G>A) pathogenic?

RORA p.Arg370His (c.1109G>A) is classified Uncertain significance in RORA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely pathogenic (0.7267); Very rare (popmax 0.00254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RORA p.Arg370His (c.1109G>A)?

RORA p.Arg370His (c.1109G>A) is associated with Inborn genetic diseases (ClinVar).

How common is RORA p.Arg370His (c.1109G>A) in the general population?

RORA p.Arg370His (c.1109G>A) is very rare (popmax 0.00254%, nfe) (gnomAD).

What do computational predictors say about RORA p.Arg370His (c.1109G>A)?

AlphaMissense predicts likely pathogenic (score 0.7267) — an in-silico prediction, not a clinical call.

RORA p.Arg370His

c.1109G>A · rs201150566 · VCV3155736

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7267 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7267	likely pathogenic
REVEL	0.9	moderately pathogenic-leaning
SaProt	LLR -11.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.40 · evaluated, not missing
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	34.0	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

Grpmax group 0.00254% European (non-Finnish) · 30/1,179,756 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00157%

Overall 0.00198% 32/1,613,674 alleles · very rare exomes 30/1,461,570 · genomes 2/152,104 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00254%	39,325
Remaining individualsnot grpmax-eligible	0.0016%	62,478
South Asian	0.0011%	91,082

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.Arg370His
Coding: c.1109G>A
MANE Select: NM_134261
dbSNP: rs201150566
Type: single nucleotide variant
Location: chr15:60502834 (GRCh38)
Gene constraint: LOEUF 0.207 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.40 · 3 PDB
Residue 370: the nr lbd domain; an α-helix

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.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
RORA p.Asp21Gly 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-arg370his (accessed [today's date]).

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