MFAP4

Chr 17

microfibril associated protein 4

NCBI Gene: 4239 ENSG00000166482 UniProt: P55083 OMIM: 600596

This gene encodes a microfibril-associated protein that binds collagen and carbohydrates and contributes to elastic fiber assembly and maintenance in the extracellular matrix. Mutations cause autosomal recessive developmental delay, intellectual disability, distinctive facial features, and connective tissue abnormalities including joint hypermobility and skin hyperextensibility. The gene has moderate constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein with similarity to a bovine microfibril-associated protein. The protein has binding specificities for both collagen and carbohydrate. It is thought to be an extracellular matrix protein which is involved in cell adhesion or intercellular interactions. The gene is located within the Smith-Magenis syndrome region. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.67

Clinical Summary— MFAP4

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

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ClinVar Variants

33 VUS of 43 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.67LOEUF

pLI 0.114

Z-score 2.43

OE 0.29 (0.14–0.67)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.35Z-score

OE missense 0.70 (0.61–0.82)

117 obs / 166.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.14–0.67)

0≤0.351.4

Missense OE?0.70 (0.61–0.82)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 4 / 13.7Missense obs/exp: 117 / 166.0Syn Z: -0.26

This gene — mechanism propensity

0.75top 25%

GOF

0.73top 25%

LOF

0.1895th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

43 submitted variants in ClinVar

ClinVar

Classification Summary

VUS33

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	33	33
Likely Benign	1	1
Benign	0	0
Total	34	34

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

View in ClinVar →

99 pathogenic / likely-pathogenic (of 113) ClinVar copy-number / structural variants overlap MFAP4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →