FECH

Chr 18AR

ferrochelatase

Also known as: EPP, EPP1, FCE

NCBI Gene: 2235 ENSG00000066926 UniProt: P22830 OMIM: 612386

The mitochondrial enzyme ferrochelatase catalyzes the insertion of ferrous iron into protoporphyrin IX in the final step of heme biosynthesis. Mutations cause erythropoietic protoporphyria, a metabolic disorder characterized by painful photosensitivity and potential liver complications, inherited in an autosomal recessive pattern. The gene shows low constraint to loss-of-function variants (pLI 0.003, LOEUF 0.616), consistent with the recessive inheritance pattern.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is localized to the mitochondrion, where it catalyzes the insertion of the ferrous form of iron into protoporphyrin IX in the heme synthesis pathway. Mutations in this gene are associated with erythropoietic protoporphyria. Two transcript variants encoding different isoforms have been found for this gene. A pseudogene of this gene is found on chromosome 3.[provided by RefSeq, May 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Protoporphyria, erythropoietic, 1MIM #177000

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · protoporphyria, erythropoietic, 1 · AR · ClinGen 2023

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.62

LOEUF

—

Mechanism

📖

GeneReview available — FECH

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.62LOEUF

pLI 0.003

Z-score 3.03

OE 0.35 (0.21–0.62)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.34Z-score

OE missense 0.75 (0.67–0.85)

175 obs / 232.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.21–0.62)

0≤0.351.4

Missense OE?0.75 (0.67–0.85)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 9 / 25.5Missense obs/exp: 175 / 232.4Syn Z: 0.65

Background carrier burden — how many people carry a rare variant somewhere in FECH?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 100

478 rare PASS variants

Rare truncating (LoF)

1 in 1,800

86 rare PASS variants

Rare synonymous (reference)

1 in 150

191 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FECH. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 140	1 in 1,500
South Asian	~43k	1 in 120	1 in 3,900
Remaining (unassigned)	~30k	1 in 91	1 in 3,000
European (Finnish)	~27k	1 in 640	≈ 1 in 13,000
Admixed American	~22k	1 in 130	1 in 2,200
African / African American	~21k	1 in 120	1 in 2,900
East Asian	~20k	1 in 110	1 in 1,500
Ashkenazi Jewish	~13k	1 in 650	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 180	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 10 of 11 coding exons well covered in gnomAD exomes; exon 7 marginal. Genomes: all 11.? see exons ↓