# NM_000140.5(FECH):c.490C>T (p.Arg164Trp)

https://sugi.bio/variant/fech-p-arg164trp

## Summary

**FECH p.Arg164Trp (c.490C>T)** is classified **Uncertain significance** in FECH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-10). AlphaMissense: likely pathogenic (0.9689); Very rare (popmax 0.00329%, sas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs750467706 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00329%, sas)

## For patients & families {#patients}

This is a change in the FECH gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.*

**Support & next steps:** [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.Arg164Trp |
| Coding change (HGVS c.) | c.490C>T |
| MANE Select transcript | [NM_000140](https://www.ncbi.nlm.nih.gov/nuccore/NM_000140) |
| dbSNP | [rs750467706](https://www.ncbi.nlm.nih.gov/snp/rs750467706/) |
| Variant type | single nucleotide variant |
| Location | chr18:57566555-57566555 (GRCh38) |
| ClinVar | [VCV2138161](https://www.ncbi.nlm.nih.gov/clinvar/variation/2138161/) |

**All HGVS expressions:** `LRG_1080:g.25183C>T`, `LRG_1080t1:c.490C>T`, `LRG_1080t2:c.508C>T`, `NC_000018.10:g.57566555G>A`, `NC_000018.9:g.55233787G>A`, `NG_008175.1:g.25183C>T`, `NM_000140.5:c.490C>T`, `NM_001012515.4:c.508C>T`, `NM_001371094.1:c.490C>T`, `NM_001371095.1:c.274C>T`, `NM_001374778.1:c.490C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9689)
- REVEL 0.967 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.019 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.799, GERP 1.89, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 35.0**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.85 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00329%** (sas) · FAF95 0.000875% · FAF99 0.000443% · 3/91,086 in the highest group · 15/1,614,134 alleles overall — very rare (popmax 0.00329%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00329% | 30,362 |
| African / African-American | 0.00133% | 75,026 |
| European (non-Finnish) | 0.000932% | 107,272 |

*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 **164** lies in a β-strand.

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-09-10.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-10 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related FECH variant pages (same residue, condition, or type): [FECH p.Arg164Gln](/variant/fech-p-arg164gln), [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 c.599-2A>G](/variant/fech-c-599-minus-2a-g), [FECH c.913-2A>G](/variant/fech-c-913-minus-2a-g), [FECH p.Arg115Ter](/variant/fech-p-arg115ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 2138161). 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.*