Is RORC p.Ala63Val (c.188C>T) pathogenic?

RORC p.Ala63Val (c.188C>T) is classified Conflicting classifications of pathogenicity in RORC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-04-12). AlphaMissense: likely benign (0.056); Ultra-rare (popmax 0.0171%, mid); Associated with autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency.

How common is RORC p.Ala63Val (c.188C>T) in the general population?

RORC p.Ala63Val (c.188C>T) is ultra-rare (popmax 0.0171%, mid) (gnomAD).

What do computational predictors say about RORC p.Ala63Val (c.188C>T)?

AlphaMissense predicts likely benign (score 0.056) — an in-silico prediction, not a clinical call.

RORC p.Ala63Val

Q: What condition is associated with RORC p.Ala63Val (c.188C>T)?

RORC p.Ala63Val (c.188C>T) is associated with autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency (ClinVar).

Q: How is Mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency inherited?

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

c.188C>T · rs143596741 · VCV1013992

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.056 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0171%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency

Computational evidence

Protein change
AlphaMissense	0.056	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -6.18	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 4.2	GERP -3.8, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 2,118 bp · p 0.0015 · regional, not allelic
Overall
CADD	17.18	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 0.0171% Middle Eastern · 1/5,864 alleles

Filtering AF 0.00351% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00243% 38/1,565,566 alleles · ultra-rare exomes 28/1,413,230 · genomes 10/152,336 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0171%	5,864
African / African-American	0.00812%	12,310
European (non-Finnish)	0.00252%	39,710
Remaining individualsnot grpmax-eligible	0.00166%	60,232
South Asian	0.00118%	84,570

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.Ala63Val
Coding: c.188C>T
MANE Select: NM_005060
dbSNP: rs143596741
Type: single nucleotide variant
Location: chr1:151816774 (GRCh38)
Gene constraint: LOEUF 0.351 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 162 PDB
Residue 63: a DNA-binding region

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

Disease context

autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

RORC p.Ala63Thr Uncertain significance ★ ⚠ same residue
RORC p.Ala63= Likely benign ★ same residue
RORC p.Arg10Gln Uncertain significance ★★ ⚠ same condition
RORC p.Arg13Trp 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

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-ala63val (accessed [today's date]).

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