Is RFXAP p.Pro99= (c.297G>A) pathogenic?

RFXAP p.Pro99= (c.297G>A) is classified Likely benign in RFXAP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-07). Ultra-rare (popmax 0.0167%, mid); Associated with MHC class II deficiency.

What condition is associated with RFXAP p.Pro99= (c.297G>A)?

RFXAP p.Pro99= (c.297G>A) is associated with MHC class II deficiency (ClinVar).

How common is RFXAP p.Pro99= (c.297G>A) in the general population?

RFXAP p.Pro99= (c.297G>A) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

RFXAP p.Pro99=

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.297G>A · rs183370317 · VCV2175424

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Conditions

MHC class II deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -3
Overall
CADD	8.873	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Middle Eastern · 1/5,984 alleles

Overall 7.16e-05% 1/1,396,368 alleles · ultra-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: RFXAP
Protein: p.Pro99=
Coding: c.297G>A
MANE Select: NM_000538
dbSNP: rs183370317
Type: single nucleotide variant
Location: chr13:36819654 (GRCh38)
Gene constraint: LOEUF 1.454 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.51 · 1 PDB
Residue 99: the 'disordered' region; a UniProt-annotated variant site (in mhc2d4; likely pathogenic)

Full RFXAP 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

RFXAP p.Arg220Cys Uncertain significance ★★ ⚠ same condition
RFXAP p.Asp91Glu Uncertain significance ★★ ⚠ same condition
RFXAP p.Glu114Val Uncertain significance ★★ ⚠ same condition
RFXAP p.Gly120Ser Uncertain significance ★★ ⚠ same condition
RFXAP p.Gly134Glu Uncertain significance ★★ ⚠ same condition
RFXAP p.Gly54Arg Uncertain significance ★★ ⚠ same condition
RFXAP p.Gly5Val Uncertain significance ★★ ⚠ same condition
RFXAP p.Ile209Val 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/rfxap-p-pro99 (accessed [today's date]).

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