RFXAP

Chr 13

regulatory factor X associated protein

Also known as: MHC2D4

NCBI Gene: 5994 ENSG00000133111 UniProt: O00287

The encoded protein forms part of the RFX transcriptional complex that binds to X-box motifs in MHC class II gene promoters and activates their transcription. Mutations cause MHC class II deficiency (bare lymphocyte syndrome type II), a severe combined immunodeficiency presenting in early infancy with recurrent infections. This follows autosomal recessive inheritance.

ResearchSummary from RefSeq, OMIM, UniProt

Major histocompatibility (MHC) class II molecules are transmembrane proteins that have a central role in development and control of the immune system. The protein encoded by this gene, along with regulatory factor X-associated ankyrin-containing protein and regulatory factor-5, forms a complex that binds to the X box motif of certain MHC class II gene promoters and activates their transcription. Once bound to the promoter, this complex associates with the non-DNA-binding factor MHC class II transactivator, which controls the cell type specificity and inducibility of MHC class II gene expression. Mutations in this gene have been linked to bare lymphocyte syndrome type II, complementation group D. Transcript variants utilizing different polyA signals have been found for this gene. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtMHC class II deficiency 4

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · MHC class II deficiency · AR · ClinGen 2023

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.98

LOEUF

—

Mechanism

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.98LOEUF

pLI 0.023

Z-score 1.62

OE 0.43 (0.21–0.98)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.04Z-score

OE missense 0.75 (0.63–0.88)

99 obs / 132.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.21–0.98)

0≤0.351.4

Missense OE?0.75 (0.63–0.88)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 4 / 9.4Missense obs/exp: 99 / 132.6Syn Z: 0.19

Background carrier burden — how many people carry a rare variant somewhere in RFXAP?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 280

362 rare PASS variants

Rare truncating (LoF)

1 in 2,000

58 rare PASS variants

Rare synonymous (reference)

1 in 180

169 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RFXAP. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 360	1 in 3,200
South Asian	~43k	1 in 190	≈ 1 in 10,000
Remaining (unassigned)	~30k	1 in 170	1 in 3,600
European (Finnish)	~27k	1 in 2,100	≈ 1 in 8,000
Admixed American	~22k	1 in 220	1 in 3,700
African / African American	~21k	1 in 300	≈ 1 in 5,800
East Asian	~20k	1 in 190	≈ 1 in 7,700
Ashkenazi Jewish	~13k	1 in 2,000	≈ 1 in 11,000
Middle Eastern	~2,884	1 in 280	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓