Is RORC p.Lys469Arg (c.1406A>G) pathogenic?

RORC p.Lys469Arg (c.1406A>G) is classified Benign in RORC (ClinVar, Single submitter, 2 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0781); Ultra-rare (popmax 0.0731%, nfe); Associated with autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency.

How common is RORC p.Lys469Arg (c.1406A>G) in the general population?

RORC p.Lys469Arg (c.1406A>G) is ultra-rare (popmax 0.0731%, nfe) (gnomAD).

What do computational predictors say about RORC p.Lys469Arg (c.1406A>G)?

AlphaMissense predicts likely benign (score 0.0781) — an in-silico prediction, not a clinical call.

RORC p.Lys469Arg

Q: What condition is associated with RORC p.Lys469Arg (c.1406A>G)?

RORC p.Lys469Arg (c.1406A>G) 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.1406A>G · rs200531029 · VCV712886

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0781 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0731%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0781	likely benign
REVEL	0.348	indeterminate
SaProt	LLR -0.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.5, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 5,488 bp · p 0.029 · regional, not allelic
Overall
CADD	21.2	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 0.0731% European (non-Finnish) · 862/1,179,992 alleles

Filtering AF 0.069% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0674%

Overall 0.263% 4,244/1,614,110 alleles · ultra-rare exomes 3,509/1,461,804 · genomes 735/152,306 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	5.11%	20
Remaining individualsnot grpmax-eligible	0.155%	644
European (non-Finnish)grpmax	0.0731%	1,369
Admixed American	0.015%	6,669
African / African-American	0.00533%	18,763
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596

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.Lys469Arg
Coding: c.1406A>G
MANE Select: NM_005060
dbSNP: rs200531029
Type: single nucleotide variant
Location: chr1:151807623 (GRCh38)
Gene constraint: LOEUF 0.351 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.42 · 162 PDB
Residue 469: the nr lbd domain

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.Lys469Asn Uncertain significance ★ 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
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-lys469arg (accessed [today's date]).

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