Is RORA p.Ile280Val (c.838A>G) pathogenic?

RORA p.Ile280Val (c.838A>G) is classified Uncertain significance in RORA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-02). AlphaMissense: likely benign (0.0989); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with RORA p.Ile280Val (c.838A>G)?

RORA p.Ile280Val (c.838A>G) is associated with Inborn genetic diseases (ClinVar).

How common is RORA p.Ile280Val (c.838A>G) in the general population?

RORA p.Ile280Val (c.838A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about RORA p.Ile280Val (c.838A>G)?

AlphaMissense predicts likely benign (score 0.0989) — an in-silico prediction, not a clinical call.

RORA p.Ile280Val

c.838A>G · VCV3434837

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0989	likely benign
REVEL	0.409	indeterminate
SaProt	LLR -7.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 7.3, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 14 kb · p 1.2e-11 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 · 1/91,076 alleles

Overall 0.000124% 2/1,613,998 alleles · very rare exomes 2/1,461,708 · genomes 0/152,290 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,076
European (non-Finnish)	8.48e-05%	1,179,894

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.Ile280Val
Coding: c.838A>G
MANE Select: NM_134261
Type: single nucleotide variant
Location: chr15:60505612 (GRCh38)
Gene constraint: LOEUF 0.207 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.40 · 3 PDB
Residue 280: 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-ile280val (accessed [today's date]).

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