Is RORC p.Ala141Thr (c.421G>A) pathogenic?

RORC p.Ala141Thr (c.421G>A) is classified Uncertain significance in RORC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-07). AlphaMissense: likely benign (0.0631); Ultra-rare (popmax 0.0298%, sas); Associated with Inborn genetic diseases.

What condition is associated with RORC p.Ala141Thr (c.421G>A)?

RORC p.Ala141Thr (c.421G>A) is associated with Inborn genetic diseases (ClinVar).

How common is RORC p.Ala141Thr (c.421G>A) in the general population?

RORC p.Ala141Thr (c.421G>A) is ultra-rare (popmax 0.0298%, sas) (gnomAD).

What do computational predictors say about RORC p.Ala141Thr (c.421G>A)?

AlphaMissense predicts likely benign (score 0.0631) — an in-silico prediction, not a clinical call.

RORC p.Ala141Thr

c.421G>A · VCV4629327

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0631 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0298%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0631	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -6.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Regional constraint	o/e 0.82	unconstrained · MANE · 2,118 bp · p 0.0015 · regional, not allelic
Overall
CADD	8.464	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 0.0298% South Asian · 27/90,644 alleles

Filtering AF 0.0209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.0018% 29/1,608,602 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0298%	3,357
Remaining individualsnot grpmax-eligible	0.00161%	62,154
European (non-Finnish)	8.5e-05%	1,176,657

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.Ala141Thr
Coding: c.421G>A
MANE Select: NM_005060
Type: single nucleotide variant
Location: chr1:151815303 (GRCh38)
Gene constraint: LOEUF 0.351 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 162 PDB
Residue 141: the 'disordered' region

Full RORC 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

RORC p.Ala141Val Uncertain significance ★ ⚠ same residue
RORC p.Ala141= Likely benign ★ same residue
RORC p.Arg10Gln Uncertain significance ★★ ⚠ same condition
RORC p.Arg208Gln Uncertain significance ★★ ⚠ same condition
RORC p.Arg237Ser Uncertain significance ★★ ⚠ same condition
RORC p.Arg257His Uncertain significance ★★ ⚠ same condition
RORC p.Arg288Gln Uncertain significance ★★ ⚠ same condition
RORC p.Arg82Gln Uncertain significance ★★ ⚠ 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/rorc-p-ala141thr (accessed [today's date]).

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