Is RORC p.Arg7Lys (c.20G>A) pathogenic?

RORC p.Arg7Lys (c.20G>A) is classified Uncertain significance in RORC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-09). AlphaMissense: likely benign (0.1128); Very rare (popmax 0.00169%, nfe); Associated with autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency.

How common is RORC p.Arg7Lys (c.20G>A) in the general population?

RORC p.Arg7Lys (c.20G>A) is very rare (popmax 0.00169%, nfe) (gnomAD).

What do computational predictors say about RORC p.Arg7Lys (c.20G>A)?

AlphaMissense predicts likely benign (score 0.1128) — an in-silico prediction, not a clinical call.

RORC p.Arg7Lys

Q: What condition is associated with RORC p.Arg7Lys (c.20G>A)?

RORC p.Arg7Lys (c.20G>A) 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.20G>A · rs764892778 · VCV648947

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1128 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

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	0.1128	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -6.75	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 0.19	GERP 1.4, phastCons 0.97
Regional constraint	o/e 1.02	unconstrained · MANE · 2,316 bp · p 0.94 · regional, not allelic
Overall
CADD	20.6	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 0.00169% European (non-Finnish) · 20/1,179,976 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.0013% 21/1,610,186 alleles · very rare exomes 18/1,457,990 · genomes 3/152,196 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00169%	58,999
Remaining individualsnot grpmax-eligible	0.0016%	62,454

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.Arg7Lys
Coding: c.20G>A
MANE Select: NM_005060
dbSNP: rs764892778
Type: single nucleotide variant
Location: chr1:151831745 (GRCh38)
Gene constraint: LOEUF 0.351 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 162 PDB
Residue 7: the 'modulating' 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.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
RORC p.Arg82Gln Uncertain significance ★★ ⚠ same condition
RORC p.Asn373Ser 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-arg7lys (accessed [today's date]).

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