# NM_000140.5(FECH):c.496G>A (p.Val166Ile)

https://sugi.bio/variant/fech-p-val166ile

## Summary

**FECH p.Val166Ile (c.496G>A)** is classified **Uncertain significance** in FECH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-02). AlphaMissense: likely benign (0.2046); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs377078701 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00333%, amr)

## 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 2 submitters, and is linked to Inborn genetic diseases.

*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.Val166Ile |
| Coding change (HGVS c.) | c.496G>A |
| MANE Select transcript | [NM_000140](https://www.ncbi.nlm.nih.gov/nuccore/NM_000140) |
| dbSNP | [rs377078701](https://www.ncbi.nlm.nih.gov/snp/rs377078701/) |
| Variant type | single nucleotide variant |
| Location | chr18:57566549-57566549 (GRCh38) |
| ClinVar | [VCV2224498](https://www.ncbi.nlm.nih.gov/clinvar/variation/2224498/) |

**All HGVS expressions:** `LRG_1080:g.25189G>A`, `LRG_1080t1:c.496G>A`, `LRG_1080t2:c.514G>A`, `NC_000018.10:g.57566549C>T`, `NC_000018.9:g.55233781C>T`, `NG_008175.1:g.25189G>A`, `NM_000140.5:c.496G>A`, `NM_001012515.4:c.514G>A`, `NM_001371094.1:c.496G>A`, `NM_001371095.1:c.280G>A`, `NM_001374778.1:c.496G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2046)
- REVEL 0.662 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -5.231 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 7.651, GERP 1.89, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 28.5**. 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 (C>A, Δ0.31 acceptor gain), 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 **0.00333%** (amr) · FAF95 0.000688% · FAF99 0.000539% · 2/59,994 in the highest group · 19/1,613,980 alleles overall — very rare (popmax 0.00333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00333% | 29,997 |
| East Asian | 0.00223% | 44,898 |
| African / African-American | 0.00134% | 74,898 |
| European (non-Finnish) | 0.00119% | 84,286 |
| South Asian | 0.0011% | 91,086 |

*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 **166** 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-02.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-02 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

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

## Similar variants {#similar}

Related FECH variant pages (same residue, condition, or type): [FECH p.Leu4Phe](/variant/fech-p-leu4phe), [FECH p.Lys320Arg](/variant/fech-p-lys320arg), [FECH p.Met267Thr](/variant/fech-p-met267thr), [FECH p.Ser197Thr](/variant/fech-p-ser197thr), [FECH p.Ser268Phe](/variant/fech-p-ser268phe), [FECH p.Asn105=](/variant/fech-p-asn105), [FECH p.Ala10Thr](/variant/fech-p-ala10thr), [FECH p.Arg13Ser](/variant/fech-p-arg13ser).

### 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 2224498). 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.*