# NM_000043.6(FAS):c.637C>T (p.Pro213Ser)

https://sugi.bio/variant/fas-p-pro213ser

## Summary

**FAS p.Pro213Ser (c.637C>T)** is classified **Uncertain significance** in FAS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-27). AlphaMissense: likely benign (0.0757); Very rare (popmax 0.005%, amr); Associated with autoimmune lymphoproliferative syndrome type 1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs755532307 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.005%, amr)

## For patients & families {#patients}

This is a change in the FAS gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to autoimmune lymphoproliferative syndrome type 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) | All ages |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | FAS is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Autoimmune lymphoproliferative syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Splenomegaly — Very frequent (99-80%)
- Lymphadenopathy — Very frequent (99-80%)
- Chronic noninfectious lymphadenopathy — Very frequent (99-80%)
- Autoimmunity — Very frequent (99-80%)
- Bruising susceptibility — Frequent (79-30%)
- Autoimmune hemolytic anemia — Frequent (79-30%)
- Abnormal bleeding — Frequent (79-30%)
- Neutropenia in presence of anti-neutropil antibodies — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024776/index) · [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.Pro213Ser |
| Coding change (HGVS c.) | c.637C>T |
| MANE Select transcript | [NM_000043](https://www.ncbi.nlm.nih.gov/nuccore/NM_000043) |
| dbSNP | [rs755532307](https://www.ncbi.nlm.nih.gov/snp/rs755532307/) |
| Variant type | single nucleotide variant |
| Location | chr10:89012067-89012067 (GRCh38) |
| ClinVar | [VCV1347150](https://www.ncbi.nlm.nih.gov/clinvar/variation/1347150/) |

**All HGVS expressions:** `LRG_134:g.26537C>T`, `NC_000010.10:g.90771824C>T`, `NC_000010.11:g.89012067C>T`, `NG_009089.2:g.26537C>T`, `NM_000043.6:c.637C>T`, `NM_001320619.2:c.568+1252C>T`, `NM_152871.4:c.574C>T`, `NM_152872.4:c.637C>T`, `NR_028033.4:n.544C>T`, `NR_028034.4:n.406C>T`, `NR_028035.4:n.469C>T`, `NR_028036.4:n.607C>T`, `NR_135314.2:n.803C>T`, `NR_135315.2:n.556C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0757)
- REVEL 0.152 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.956 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -1.919, GERP -1.74 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.093**. 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 0.92** across the covering region of the MANE Select transcript (88,990,877–89,014,218), spanning 23,341 bp. Chi-square p 0.16. 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 **0.005%** (amr) · FAF95 0.00133% · FAF99 0.000668% · 3/59,988 in the highest group · 4/1,613,328 alleles overall — very rare (popmax 0.005%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.005% | 19,996 |
| European (non-Finnish) | 8.48e-05% | 1,179,436 |

*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}

Residue **213** lies in the 'interaction with hipk3' region.

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. p.Pro213Ser falls in the interaction with hipk3 region.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-02-27.

**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 | 2021-02-27 |

## Associated conditions {#conditions}

[autoimmune lymphoproliferative syndrome type 1](https://sugi.bio/atlas/disease/autoimmune-lymphoproliferative-syndrome-type-1/).

**Reported phenotype names (ClinVar):** Autoimmune lymphoproliferative syndrome type 1, AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE I, AUTOSOMAL DOMINANT.

## Similar variants {#similar}

Related FAS variant pages (same residue, condition, or type): [FAS c.651+1G>A](/variant/fas-c-651-plus-1g-a), [FAS c.651+2T>C](/variant/fas-c-651-plus-2t-c), [FAS p.Arg250Gln](/variant/fas-p-arg250gln), [FAS p.Arg250Gly](/variant/fas-p-arg250gly), [FAS p.Arg250Ter](/variant/fas-p-arg250ter), [FAS p.Asp260Asn](/variant/fas-p-asp260asn), [FAS p.Cys135Tyr](/variant/fas-p-cys135tyr), [FAS p.Glu272Lys](/variant/fas-p-glu272lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 1347150). 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.*