Is RORC p.Arg473Trp (c.1417C>T) pathogenic?

RORC p.Arg473Trp (c.1417C>T) is classified Uncertain significance in RORC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-19). AlphaMissense: likely benign (0.1531); Very rare (popmax 0.000169%, nfe).

How common is RORC p.Arg473Trp (c.1417C>T) in the general population?

RORC p.Arg473Trp (c.1417C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about RORC p.Arg473Trp (c.1417C>T)?

AlphaMissense predicts likely benign (score 0.1531) — an in-silico prediction, not a clinical call.

RORC p.Arg473Trp

c.1417C>T · VCV4911003

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1531 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1531	likely benign
REVEL	0.889	moderately pathogenic-leaning
SaProt	LLR -8.39	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.53 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 0.33, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 5,488 bp · p 0.029 · regional, not allelic
Overall
CADD	27.7	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 0.000169% European (non-Finnish) · 2/1,180,014 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,156 alleles · very rare exomes 3/1,461,842 · genomes 0/152,314 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,016
European (non-Finnish)grpmax	0.000169%	590,005

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: RORC
Protein: p.Arg473Trp
Coding: c.1417C>T
MANE Select: NM_005060
Type: single nucleotide variant
Location: chr1:151807612 (GRCh38)
Gene constraint: LOEUF 0.351 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 162 PDB
Residue 473: the nr lbd domain; an α-helix

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

Similar variants

RORC p.Arg10Gln Uncertain significance ★★ ⚠ same type
RORC p.Arg13Trp Uncertain significance ★★ ⚠ same type
RORC p.Arg208Gln Uncertain significance ★★ ⚠ same type
RORC p.Arg237Ser Uncertain significance ★★ ⚠ same type
RORC p.Arg257His Uncertain significance ★★ ⚠ same type
RORC p.Arg288Gln Uncertain significance ★★ ⚠ same type
RORC p.Arg82Gln Uncertain significance ★★ ⚠ same type
RORC p.Asn373Ser 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/rorc-p-arg473trp (accessed [today's date]).

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