MS4A4A

Chr 11

membrane spanning 4-domains A4A

Also known as: 4SPAN1, CD20-L1, CD20L1, HDCME31P, MS4A4, MS4A7

NCBI Gene: 51338ENSG00000110079UniProt: Q96JQ5

This gene encodes a member of the membrane-spanning 4A gene family. Members of this nascent protein family are characterized by common structural features, similar intron/exon splice boundaries, and display unique expression patterns in hematopoietic cells and nonlymphoid tissues. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

47
ClinVar variants
10
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— MS4A4A
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
10 Pathogenic / Likely Pathogenic· 34 VUS of 47 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.35LOEUF
pLI 0.000
Z-score 0.70
OE 0.78 (0.47–1.35)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.25Z-score
OE missense 0.94 (0.81–1.09)
118 obs / 125.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.78 (0.47–1.35)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.81–1.09)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.94
0≤1.21.6
LoF obs/exp: 9 / 11.6Missense obs/exp: 118 / 125.9Syn Z: 0.30

ClinVar Variant Classifications

47 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6
Likely Pathogenic4
VUS34
Likely Benign2
Benign1
6
Pathogenic
4
Likely Pathogenic
34
VUS
2
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
6
0
6
Likely Pathogenic
0
0
4
0
4
VUS
0
30
4
0
34
Likely Benign
0
1
1
0
2
Benign
0
1
0
0
1
Total03215047

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

MS4A4A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Targeting MS4A4A on tumour-associated macrophages restores CD8+ T-cell-mediated antitumour immunity.
Li Y et al.·Gut
2023
Integrating single-cell and spatial analysis reveals MUC1-mediated cellular crosstalk in mucinous colorectal adenocarcinoma.
Zhou H et al.·Clin Transl Med
2024
Targeting MS4A4A: A novel pathway to improve immunotherapy responses in glioblastoma.
Shao G et al.·CNS Neurosci Ther
2024
Ms4a4a deficiency ameliorates plaque pathology in a mouse model of amyloid accumulation.
Danhash EP et al.·Alzheimers Dement
2025Functional
GBP2 promotes M1 macrophage polarization by activating the notch1 signaling pathway in diabetic nephropathy.
Li X et al.·Front Immunol
2023
The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk.
Deming Y et al.·Sci Transl Med
2019
Integration of Alzheimer's disease genetics and myeloid genomics identifies disease risk regulatory elements and genes.
Novikova G et al.·Nat Commun
2021
Monocyte-macrophage membrane expression of IL-1R2 is a severity biomarker in sepsis.
Supino D et al.·Cell Death Dis
2025
MS4A4A-positive tumor-associated macrophages associate with poor prognosis and T-cell exhaustion in patients with urothelial carcinoma of the bladder.
Yang T et al.·J Pathol
2025Cohort
Novel insights into molecular signatures and pathogenic cell populations shared by systemic lupus erythematosus and vascular dementia.
Chen J et al.·Funct Integr Genomics
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools