Is RORA p.Arg140Gln (c.419G>A) pathogenic?

RORA p.Arg140Gln (c.419G>A) is classified Uncertain significance in RORA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). AlphaMissense: likely pathogenic (0.993); Very rare (popmax 0.0011%, sas).

How common is RORA p.Arg140Gln (c.419G>A) in the general population?

RORA p.Arg140Gln (c.419G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about RORA p.Arg140Gln (c.419G>A)?

AlphaMissense predicts likely pathogenic (score 0.993) — an in-silico prediction, not a clinical call.

RORA p.Arg140Gln

c.419G>A · rs780606205 · VCV3253371

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.993 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.993	likely pathogenic
REVEL	0.734	pathogenic-leaning
SaProt	LLR -14.06	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 7.7	GERP 7.3, phastCons 1
Regional constraint	o/e 0.28	constrained · MANE · 167 kb · p 9.4e-16 · regional, not allelic
Overall
CADD	33.0	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 0.0011% South Asian · 1/91,064 alleles

Overall 0.000186% 3/1,614,006 alleles · very rare exomes 3/1,461,716 · genomes 0/152,290 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,036
South Asiangrpmax	0.0011%	91,064
European (non-Finnish)	8.48e-05%	1,179,908

Finnish 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.Arg140Gln
Coding: c.419G>A
MANE Select: NM_134261
dbSNP: rs780606205
Type: single nucleotide variant
Location: chr15:60514621 (GRCh38)
Gene constraint: LOEUF 0.207 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.40 · 3 PDB

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

Similar variants

RORA p.Arg140Ter Likely pathogenic ★ same residue
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

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-arg140gln (accessed [today's date]).

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