SUMF1

Chr 3

sulfatase modifying factor 1

Also known as: AAPA3037, FGE, UNQ3037

NCBI Gene: 285362 ENSG00000144455 UniProt: Q8NBK3

This gene encodes formylglycine-generating enzyme, which activates sulfatases by oxidizing a cysteine residue to form the essential 3-oxoalanine (formylglycine) residue required for sulfatase activity. Mutations cause multiple sulfatase deficiency, an autosomal recessive lysosomal storage disorder characterized by combined deficiency of all cellular sulfatases. The pathogenic mechanism involves loss of sulfatase activation, leading to accumulation of sulfated substrates and progressive neurodegeneration.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an enzyme that catalyzes the hydrolysis of sulfate esters by oxidizing a cysteine residue in the substrate sulfatase to an active site 3-oxoalanine residue, which is also known as C-alpha-formylglycine. Mutations in this gene cause multiple sulfatase deficiency, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 1.07

Clinical Summary— SUMF1

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Gene-Disease Validity (ClinGen)

mucosulfatidosis · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

158 unique Pathogenic / Likely Pathogenic· 314 VUS of 934 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SUMF1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.07LOEUF

pLI 0.000

Z-score 1.31

OE 0.69 (0.46–1.07)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.50Z-score

OE missense 1.10 (0.98–1.22)

236 obs / 215.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.69 (0.46–1.07)

0≤0.351.4

Missense OE?1.10 (0.98–1.22)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 15 / 21.6Missense obs/exp: 236 / 215.4Syn Z: -0.76

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSUMF1-related multiple sulfatase deficiencyLOFAR

This gene — mechanism propensity

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

0.6261th %ile

GOF

0.6052th %ile

LOF

0.3453th %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

934 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic74

Likely Pathogenic84

VUS314

Likely Benign376

Benign40

Conflicting32

Pathogenic

Likely Pathogenic

314

VUS

376

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	52	3	19	0	74
Likely Pathogenic	51	26	7	0	84
VUS	3	257	48	6	314
Likely Benign	1	6	157	212	376
Benign	0	5	33	2	40
Conflicting	—				32
Total	107	297	264	220	920

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

View in ClinVar →

85 pathogenic / likely-pathogenic (of 127) ClinVar copy-number / structural variants overlap SUMF1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →