Is RORA p.Arg46Ser (c.136C>A) pathogenic?

RORA p.Arg46Ser (c.136C>A) is classified Conflicting classifications of pathogenicity in RORA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-11-01). AlphaMissense: likely benign (0.3342); Very rare (popmax 0.0035%, nfe); Associated with neurofibromatosis type 1.

What condition is associated with RORA p.Arg46Ser (c.136C>A)?

RORA p.Arg46Ser (c.136C>A) is associated with neurofibromatosis type 1 (ClinVar).

How common is RORA p.Arg46Ser (c.136C>A) in the general population?

RORA p.Arg46Ser (c.136C>A) is very rare (popmax 0.0035%, nfe) (gnomAD).

How is Neurofibromatosis type 1 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RORA p.Arg46Ser (c.136C>A)?

AlphaMissense predicts likely benign (score 0.3342) — an in-silico prediction, not a clinical call.

RORA p.Arg46Ser

c.136C>A · VCV4074930

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3342 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0035%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

neurofibromatosis type 1

Computational evidence

Protein change
AlphaMissense	0.3342	likely benign
REVEL	0.376	indeterminate
SaProt	LLR -5.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.76	donor gain · deltas
Pangolin	Δ0.32	gain · loss 0.11 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9	GERP 2.7, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 551 kb · p 0.0056 · regional, not allelic
Overall
CADD	24.4	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 0.0035% European (non-Finnish) · 40/1,142,096 alleles

Filtering AF 0.00264% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00232%

Overall 0.00267% 41/1,536,968 alleles · very rare exomes 41/1,388,184 · genomes 0/148,784 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0035%	28,552
African / African-American	0.0014%	71,222

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.Arg46Ser
Coding: c.136C>A
MANE Select: NM_134261
Type: single nucleotide variant
Location: chr15:61229083 (GRCh38)
Gene constraint: LOEUF 0.207 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.40 · 3 PDB
Residue 46: the 'disordered' region

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

Disease context

neurofibromatosis type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Neurofibromatosis type 1 (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal
Prevalence: 1-5 / 10 000 (United Kingdom)

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-arg46ser (accessed [today's date]).

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