# NM_000043.6(FAS):c.191del (p.Pro64fs)

https://sugi.bio/variant/fas-p-pro64fs

## Summary

**FAS p.Pro64fs (c.191del)** is classified **Likely pathogenic** in FAS (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-08). No gnomAD frequency available for this variant; Associated with FAS-related disorder.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1589465256 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the FAS gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to FAS-related disorder.

*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 | [FAS](https://sugi.bio/atlas/gene/FAS/) |
| Protein change (HGVS p.) | p.Pro64fs |
| Coding change (HGVS c.) | c.191del |
| MANE Select transcript | [NM_000043](https://www.ncbi.nlm.nih.gov/nuccore/NM_000043) |
| dbSNP | [rs1589465256](https://www.ncbi.nlm.nih.gov/snp/rs1589465256/) |
| Variant type | Deletion |
| Location | chr10:89003188-89003188 (GRCh38) |
| ClinVar | [VCV636739](https://www.ncbi.nlm.nih.gov/clinvar/variation/636739/) |

**All HGVS expressions:** `LRG_134:g.17659del`, `LRG_134t1:c.191del`, `NC_000010.10:g.90762946del`, `NC_000010.11:g.89003189del`, `NG_009089.2:g.17659del`, `NM_000043.6:c.191del`, `NM_001320619.2:c.191del`, `NM_152871.4:c.191del`, `NM_152872.4:c.191del`, `NR_028033.4:n.270del`, `NR_028034.4:n.270del`, `NR_028035.4:n.270del`, `NR_028036.4:n.270del`, `NR_135313.2:n.270del`, `NR_135314.2:n.357del`, `NR_135315.2:n.357del`

## 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 0.363, GERP 0.183, phastCons 0.129 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.372, pLI 0.99961), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 9**, so the transcript is predicted to undergo NMD.
- 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.
- 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}

**FAS** population constraint: LOEUF 0.372, pLI 0.99961, missense-Z 1.2561; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *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):

- **FAS-related autoimmune lymphoproliferative immune disorder** — Definitive (SD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 78.21, 40% of residues very-high.

**7 experimental structure(s)** (PDB): [1DDF](https://www.rcsb.org/structure/1DDF), [2NA7](https://www.rcsb.org/structure/2NA7), [3EWT](https://www.rcsb.org/structure/3EWT), [3EZQ](https://www.rcsb.org/structure/3EZQ), [3THM](https://www.rcsb.org/structure/3THM), [3TJE](https://www.rcsb.org/structure/3TJE).

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

*Describes the biological roles of FAS (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:** FAS's established molecular role includes tumor necrosis factor receptor activity.


### Pathways affected {#pathways}

FAS participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CASP8 activity is inhibited](https://reactome.org/content/detail/R-HSA-5218900) | curated |
| [Caspase activation via Death Receptors in the presence of ligand](https://reactome.org/content/detail/R-HSA-140534) | curated |
| [Dimerization of procaspase-8](https://reactome.org/content/detail/R-HSA-69416) | curated |
| [FasL/ CD95L signaling](https://reactome.org/content/detail/R-HSA-75157) | curated |
| [RIPK1-mediated regulated necrosis](https://reactome.org/content/detail/R-HSA-5213460) | curated |
| [Regulation by c-FLIP](https://reactome.org/content/detail/R-HSA-3371378) | curated |
| [TP53 Regulates Transcription of Death Receptors and Ligands](https://reactome.org/content/detail/R-HSA-6803211) | curated |

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

**Molecular function:** tumor necrosis factor receptor activity, calmodulin binding, kinase binding, identical protein binding.

**Biological process:** apoptotic process, extrinsic apoptotic signaling pathway via death domain receptors, regulation of stress-activated MAPK cascade, cellular response to amino acid starvation, Fas signaling pathway, positive regulation of apoptotic process.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-08-08.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2018-08-08 |

## Associated conditions {#conditions}

[FAS-related disorder](https://sugi.bio/atlas/disease/fas-related-disorder/).

**Reported phenotype names (ClinVar):** FAS-related disorder, FAS-related condition.

## Similar variants {#similar}

Related FAS variant pages (same residue, condition, or type): [FAS p.Lys193fs](/variant/fas-p-lys193fs), [FAS c.196+1G>A](/variant/fas-c-196-plus-1g-a), [FAS p.Arg250Gly](/variant/fas-p-arg250gly), [FAS p.Cys135Tyr](/variant/fas-p-cys135tyr), [FAS p.Glu272Lys](/variant/fas-p-glu272lys), [FAS p.Arg121Trp](/variant/fas-p-arg121trp), [FAS p.Thr163Ile](/variant/fas-p-thr163ile), [FAS c.569-1G>A](/variant/fas-c-569-minus-1g-a).

### 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 636739). 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.*