MEGF6

Chr 1

multiple EGF like domains 6

Also known as: EGFL3

NCBI Gene: 1953 ENSG00000162591 UniProt: O75095 OMIM: 604266

The protein is predicted to bind calcium ions and function as a scavenger receptor involved in vesicle-mediated transport in the extracellular region. The gene shows very low constraint against loss-of-function variants (pLI near zero, LOEUF 0.908), suggesting it may tolerate such variants without causing severe disease. No well-established human disease associations have been reported for mutations in this gene.

OMIM ResearchSummary from RefSeq

Predicted to enable calcium ion binding activity and scavenger receptor activity. Predicted to be involved in vesicle-mediated transport. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.91

Clinical Summary— MEGF6

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

303 VUS of 393 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?

0.91LOEUF

pLI 0.000

Z-score 2.27

OE 0.74 (0.60–0.91)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.46Z-score

OE missense 0.96 (0.91–1.01)

923 obs / 963.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.74 (0.60–0.91)

0≤0.351.4

Missense OE?0.96 (0.91–1.01)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 65 / 88.0Missense obs/exp: 923 / 963.0Syn Z: -2.15

This gene — mechanism propensity

0.5575th %ile

GOF

0.6833th %ile

LOF

0.4332th %ile

The highest-scoring mechanism for this gene is gain-of-function.

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

393 submitted variants in ClinVar

ClinVar

Classification Summary

VUS303

Likely Benign38

Benign17

Conflicting1

303

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	303	0	0	303
Likely Benign	0	25	2	11	38
Benign	0	9	0	8	17
Conflicting	—				1
Total	0	337	2	19	359

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

View in ClinVar →

99 pathogenic / likely-pathogenic (of 117) ClinVar copy-number / structural variants overlap MEGF6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →