# NM_000140.5(FECH):c.1001C>T (p.Pro334Leu)

https://sugi.bio/variant/fech-p-pro334leu

## Summary

**FECH p.Pro334Leu (c.1001C>T)** is classified **Pathogenic/Likely pathogenic** in FECH (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-19). AlphaMissense: likely pathogenic (0.9861); Ultra-rare (popmax 0.0155%, nfe); Associated with protoporphyria, erythropoietic, 1.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs150146721 · 4 submitters · 1 linked condition · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0155%, nfe)

## For patients & families {#patients}

This is a change in the FECH gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to protoporphyria, erythropoietic, 1.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | <1 / 1 000 000 (Europe) |
| Clinical trials | 29 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | FECH is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Autosomal erythropoietic protoporphyria** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Pruritus — Very frequent (99-80%)
- Cutaneous photosensitivity — Very frequent (99-80%)
- Abnormal circulating porphyrin concentration — Very frequent (99-80%)
- Erythema — Very frequent (99-80%)
- Eczematoid dermatitis — Occasional (29-5%)
- Edema — Occasional (29-5%)
- Cholelithiasis — Occasional (29-5%)
- Cirrhosis — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024616/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FECH](https://sugi.bio/atlas/gene/FECH/) |
| Protein change (HGVS p.) | p.Pro334Leu |
| Coding change (HGVS c.) | c.1001C>T |
| MANE Select transcript | [NM_000140](https://www.ncbi.nlm.nih.gov/nuccore/NM_000140) |
| dbSNP | [rs150146721](https://www.ncbi.nlm.nih.gov/snp/rs150146721/) |
| Variant type | single nucleotide variant |
| Location | chr18:57554336-57554336 (GRCh38) |
| ClinVar | [VCV375409](https://www.ncbi.nlm.nih.gov/clinvar/variation/375409/) |

**All HGVS expressions:** `LRG_1080:g.37402C>T`, `LRG_1080t1:c.1001C>T`, `LRG_1080t2:c.1019C>T`, `NC_000018.10:g.57554336G>A`, `NC_000018.9:g.55221568G>A`, `NG_008175.1:g.37402C>T`, `NM_000140.4:c.1001C>T`, `NM_000140.5:c.1001C>T`, `NM_001012515.4:c.1019C>T`, `NM_001371094.1:c.902C>T`, `NM_001371095.1:c.785C>T`, `NM_001374778.1:c.1001C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9861) — concordant with the pathogenic call
- REVEL 0.936 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.735 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.811, GERP 1.89, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in FECH (of 2,482 modeled).
- CADD: **PHRED 32.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.81** across the covering region of the MANE Select transcript (57,550,715–57,586,620), spanning 35,905 bp. Chi-square p 2e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0155%** (nfe) · FAF95 0.0137% · FAF99 0.0129% · 183/1,180,034 in the highest group · 200/1,614,156 alleles overall — ultra-rare (popmax 0.0155%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0176% | 5,683 |
| European (non-Finnish) (grpmax) | 0.0155% | 6,448 |
| Finnish (not grpmax-eligible) | 0.00312% | 32,011 |
| African / African-American | 0.00267% | 37,517 |
| East Asian | 0.00223% | 44,882 |
| South Asian | 0.0011% | 91,076 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**FECH** population constraint: LOEUF 0.859, pLI 1.0073e-07, missense-Z 1.6367. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **protoporphyria, erythropoietic, 1** — Definitive (AR)

## Protein context {#protein}

Residue **334** lies in a UniProt-annotated variant site (in epp1; enzyme retains 19% of activity).

AlphaFold model confidence (whole protein): pLDDT 87.37, 81% of residues very-high.

**25 experimental structure(s)** (PDB): [1HRK](https://www.rcsb.org/structure/1HRK), [2HRC](https://www.rcsb.org/structure/2HRC), [2HRE](https://www.rcsb.org/structure/2HRE), [2PNJ](https://www.rcsb.org/structure/2PNJ), [2PO5](https://www.rcsb.org/structure/2PO5), [2PO7](https://www.rcsb.org/structure/2PO7) — incl. mutant structure 2HRC.

## What this gene does {#gene-function}

*Describes the biological roles of FECH (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** FECH's established molecular role includes protoporphyrin ferrochelatase activity.


### Pathways affected {#pathways}

FECH participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Heme biosynthesis](https://reactome.org/content/detail/R-HSA-189451) | curated |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protoporphyrin ferrochelatase activity, identical protein binding, protein homodimerization activity.

**Biological process:** heme biosynthetic process, heme B biosynthetic process, obsolete protoporphyrinogen IX metabolic process.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-19.

**Submitter consensus:** conflicting (2 Likely pathogenic, 2 Pathogenic).

**Submission history:** 4 submissions (2016–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Knight Diagnostic Laboratories, Oregon Health and Sciences University | Likely pathogenic | criteria provided, single submitter | clinical testing | 2016-06-28 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-11 |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-03-19 |

## Associated conditions {#conditions}

[protoporphyria, erythropoietic, 1](https://sugi.bio/atlas/disease/protoporphyria-erythropoietic-1/).

**Reported phenotype names (ClinVar):** Protoporphyria, erythropoietic, 1, not provided, none provided, Erythropoietic Protoporphyria, Autosomal Recessive, FERROCHELATASE DEFICIENCY, HEME SYNTHETASE DEFICIENCY.

## Similar variants {#similar}

Related FECH variant pages (same residue, condition, or type): [FECH c.1137+3A>G](/variant/fech-c-1137-plus-3a-g), [FECH c.314+2T>G](/variant/fech-c-314-plus-2t-g), [FECH c.463+1G>C](/variant/fech-c-463-plus-1g-c), [FECH c.598+1G>T](/variant/fech-c-598-plus-1g-t), [FECH p.Arg115Ter](/variant/fech-p-arg115ter), [FECH p.Arg96Ter](/variant/fech-p-arg96ter), [FECH p.Asp274Asn](/variant/fech-p-asp274asn), [FECH p.Cys406Tyr](/variant/fech-p-cys406tyr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 375409). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*