# NM_032228.6(FAR1):c.1494del (p.Leu499fs)

https://sugi.bio/variant/far1-p-leu499fs

## Summary

**FAR1 p.Leu499fs (c.1494del)** is classified **Uncertain significance** in FAR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-23). No gnomAD frequency available for this variant.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2134204262 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the FAR1 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 | [FAR1](https://sugi.bio/atlas/gene/FAR1/) |
| Protein change (HGVS p.) | p.Leu499fs |
| Coding change (HGVS c.) | c.1494del |
| MANE Select transcript | [NM_032228](https://www.ncbi.nlm.nih.gov/nuccore/NM_032228) |
| dbSNP | [rs2134204262](https://www.ncbi.nlm.nih.gov/snp/rs2134204262/) |
| Variant type | Deletion |
| Location | chr11:13728720-13728720 (GRCh38) |
| ClinVar | [VCV1468135](https://www.ncbi.nlm.nih.gov/clinvar/variation/1468135/) |

**All HGVS expressions:** `NC_000011.10:g.13728720del`, `NC_000011.9:g.13750267del`, `NG_041826.1:g.65062del`, `NM_032228.6:c.1494del`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 11.887, GERP 1.98, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.595, pLI 0.57071. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (12 of 12)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **segmental_duplication** (chr13:90171762). Short reads may not map uniquely here, so both the call and its population frequency are less reliable. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**FAR1** population constraint: LOEUF 0.595, pLI 0.57071, missense-Z 3.7127. *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):

- **fatty acyl-CoA reductase 1 upregulation** — Moderate (AD)
- **fatty acyl-CoA reductase 1 deficiency** — Moderate (AR)

## Protein context {#protein}

Residue **499** lies in the 'necessary and sufficient for pex19-mediated localization into peroxisome membrane' region; a UniProt-annotated variant site (in pfcrd; results in a complete loss of enzyme activity).

AlphaFold model confidence (whole protein): pLDDT 94.13, 88% of residues very-high.

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

*Describes the biological roles of FAR1 (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:** FAR1's established molecular role includes alcohol-forming long-chain fatty acyl-CoA reductase (NADP+) activity. p.Leu499fs falls in the necessary and sufficient for pex19-mediated localization into peroxisome membrane region.


### Pathways affected {#pathways}

FAR1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Wax biosynthesis](https://reactome.org/content/detail/R-HSA-9640463) | curated |

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

**Molecular function:** alcohol-forming long-chain fatty acyl-CoA reductase (NADP+) activity.

**Biological process:** ether lipid biosynthetic process, long-chain fatty-acyl-CoA metabolic process, glycerophospholipid biosynthetic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-23.

**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 | 2022-08-23 |

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

## Similar variants {#similar}

Related FAR1 variant pages (same residue, condition, or type): [FAR1 p.Leu499=](/variant/far1-p-leu499), [FAR1 c.1257+16_1257+17del](/variant/far1-c-1257-plus-16-1257-plus-17del), [FAR1 c.365+9_365+10del](/variant/far1-c-365-plus-9-365-plus-10del), [FAR1 p.Lys78fs](/variant/far1-p-lys78fs), [FAR1 c.1257+8_1257+11del](/variant/far1-c-1257-plus-8-1257-plus-11del), [FAR1 c.1258-11del](/variant/far1-c-1258-minus-11del), [FAR1 c.1385+12_1385+19del](/variant/far1-c-1385-plus-12-1385-plus-19del), [FAR1 c.365+19_365+25del](/variant/far1-c-365-plus-19-365-plus-25del).

### 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 1468135). 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.*