MS4A1

Chr 11AR

membrane spanning 4-domains A1

Also known as: B1, Bp35, CD20, CVID5, FMC7, LEU-16, S7

NCBI Gene: 931 ENSG00000156738 UniProt: P11836 OMIM: 112210

This gene encodes a B-lymphocyte surface protein that functions as a store-operated calcium channel component, promoting calcium influx necessary for B-cell development, differentiation, and activation. Mutations cause common variable immunodeficiency with autosomal recessive inheritance. The gene shows low constraint to loss-of-function variation, consistent with recessive disease requiring biallelic mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the membrane-spanning 4A gene family. Members of this nascent protein family are characterized by common structural features and similar intron/exon splice boundaries and display unique expression patterns among hematopoietic cells and nonlymphoid tissues. This gene encodes a B-lymphocyte surface molecule which plays a role in the development and differentiation of B-cells into plasma cells. This family member is localized to 11q12, among a cluster of family members. Alternative splicing of this gene results in two transcript variants which encode the same protein. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Immunodeficiency, common variable, 5MIM #613495

Clinical highlights

Gene–disease validity (ClinGen)

Limited · immunodeficiency, common variable, 5 · AR · ClinGen 2022

not for standalone diagnostic reporting

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.27

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.27LOEUF

pLI 0.000

Z-score 0.93

OE 0.70 (0.41–1.27)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.14Z-score

OE missense 0.97 (0.85–1.11)

151 obs / 156.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.70 (0.41–1.27)

0≤0.351.4

Missense OE?0.97 (0.85–1.11)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 8 / 11.4Missense obs/exp: 151 / 156.0Syn Z: -0.42

Background carrier burden — how many people carry a rare variant somewhere in MS4A1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 200

371 rare PASS variants

Rare truncating (LoF)

1 in 3,500

54 rare PASS variants

Rare synonymous (reference)

1 in 490

130 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MS4A1. 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 230	1 in 3,400
South Asian	~43k	1 in 84	1 in 2,200
Remaining (unassigned)	~30k	1 in 240	1 in 3,800
European (Finnish)	~27k	1 in 510	none seen
Admixed American	~22k	1 in 210	≈ 1 in 11,000
African / African American	~21k	1 in 170	1 in 1,400
East Asian	~20k	1 in 190	≈ 1 in 20,000
Ashkenazi Jewish	~13k	≈ 1 in 4,400	none seen
Middle Eastern	~2,884	1 in 360	≈ 1 in 720

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 6 coding exons well covered in gnomAD exomes and genomes.? see exons ↓