Is RORA p.Ser39Asn (c.116G>A) pathogenic?

RORA p.Ser39Asn (c.116G>A) is classified Uncertain significance in RORA (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-16). AlphaMissense: likely benign (0.0726); Very rare (popmax 0.00396%, amr).

How common is RORA p.Ser39Asn (c.116G>A) in the general population?

RORA p.Ser39Asn (c.116G>A) is very rare (popmax 0.00396%, amr) (gnomAD).

What do computational predictors say about RORA p.Ser39Asn (c.116G>A)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

RORA p.Ser39Asn

c.116G>A · VCV4887214

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00396%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign
REVEL	0.208	benign-leaning
SaProt	LLR -8.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 1.6, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 551 kb · p 0.0056 · regional, not allelic
Overall
CADD	13.25	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 0.00396% Admixed American · 2/50,516 alleles

Filtering AF 0.000656% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000246%

Overall 0.00026% 4/1,539,738 alleles · very rare exomes 3/1,390,994 · genomes 1/148,744 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00396%	25,258
African / African-American	0.0014%	71,468
European (non-Finnish)	8.74e-05%	1,143,572

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.Ser39Asn
Coding: c.116G>A
MANE Select: NM_134261
Type: single nucleotide variant
Location: chr15:61229103 (GRCh38)
Gene constraint: LOEUF 0.207 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.40 · 3 PDB
Residue 39: the 'disordered' region

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-ser39asn (accessed [today's date]).

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