Is RFX5 p.Arg166= (c.498G>A) pathogenic?

RFX5 p.Arg166= (c.498G>A) is classified Likely benign in RFX5 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-11). Very rare (popmax 8.47e-05%, nfe); Associated with MHC class II deficiency.

What condition is associated with RFX5 p.Arg166= (c.498G>A)?

RFX5 p.Arg166= (c.498G>A) is associated with MHC class II deficiency (ClinVar).

How common is RFX5 p.Arg166= (c.498G>A) in the general population?

RFX5 p.Arg166= (c.498G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

RFX5 p.Arg166=

Q: How is Immunodeficiency by defective expression of MHC class II inherited?

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

c.498G>A · rs201026596 · VCV1103252

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

MHC class II deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.4	GERP -3.3, phastCons 1
Overall
CADD	7.601	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,036 alleles

Overall 6.84e-05% 1/1,461,876 alleles · very rare

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: RFX5
Protein: p.Arg166=
Coding: c.498G>A
MANE Select: NM_001025603
dbSNP: rs201026596
Type: single nucleotide variant
Location: chr1:151344254 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.48 · 3 PDB
Residue 166: a DNA-binding region; a β-strand

Full RFX5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MHC class II deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Immunodeficiency by defective expression of MHC class II (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

RFX5 c.555+1G>A Likely pathogenic ★★ same condition
RFX5 c.757+1G>A Pathogenic/Likely pathogenic ★★ same condition
RFX5 p.Arg239Ter Pathogenic ★★ same condition
RFX5 p.Arg294Ter Pathogenic/Likely pathogenic ★★ same condition
RFX5 p.Arg35Ter Pathogenic/Likely pathogenic ★★ same condition
RFX5 c.474-3C>A Uncertain significance ★★ same condition
RFX5 p.Ala241Val Uncertain significance ★★ ⚠ same condition
RFX5 p.Ala441Gly 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/rfx5-p-arg166 (accessed [today's date]).

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