MFF

Chr 2AR

mitochondrial fission factor

Also known as: C2orf33, EMPF2, GL004

NCBI Gene: 56947 ENSG00000168958 UniProt: Q9GZY8 OMIM: 614785

The MFF protein recruits dynamin-1-like protein to mitochondria and peroxisomes to promote fission of these organelles. Biallelic mutations cause autosomal recessive encephalopathy due to defective mitochondrial and peroxisomal fission. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.567), and the disorder primarily affects the central nervous system through disrupted cellular organelle dynamics.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This is a nuclear gene encoding a protein that functions in mitochondrial and peroxisomal fission. The encoded protein recruits dynamin-1-like protein (DNM1L) to mitochondria. There are multiple pseudogenes for this gene on chromosomes 1, 5, and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.571 OMIM phenotype

Clinical Summary— MFF

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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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

14 unique Pathogenic / Likely Pathogenic· 91 VUS of 223 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MFF

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.57LOEUF

pLI 0.065

Z-score 3.02

OE 0.29 (0.16–0.57)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.44Z-score

OE missense 0.91 (0.81–1.03)

187 obs / 204.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.16–0.57)

0≤0.351.4

Missense OE?0.91 (0.81–1.03)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 6 / 20.9Missense obs/exp: 187 / 204.9Syn Z: 0.89

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMFF-related encephalopathy due to defective mitochondrial and peroxisomal fissionLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.77top 25%

GOF

0.5759th %ile

LOF

0.3841th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

223 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic8

VUS91

Likely Benign55

Benign42

Conflicting3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	0	0	0	6
Likely Pathogenic	8	0	0	0	8
VUS	1	86	4	0	91
Likely Benign	0	4	29	22	55
Benign	0	3	38	1	42
Conflicting	—				3
Total	15	93	71	23	205

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap MFF — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →