# NM_032545.4(CFC1):c.649_655del (p.Pro217fs)

https://sugi.bio/variant/cfc1-p-pro217fs

## Summary

**CFC1 p.Pro217fs (c.649_655del)** is classified **Uncertain significance** in CFC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-01). Ultra-rare (popmax 0.0148%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · ultra-rare (popmax 0.0148%, amr)

## For patients & families {#patients}

This is a change in the CFC1 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 | [CFC1](https://sugi.bio/atlas/gene/CFC1/) |
| Protein change (HGVS p.) | p.Pro217fs |
| Coding change (HGVS c.) | c.649_655del |
| MANE Select transcript | [NM_032545](https://www.ncbi.nlm.nih.gov/nuccore/NM_032545) |
| Variant type | Deletion |
| Location | chr2:130592894-130592900 (GRCh38) |
| ClinVar | [VCV3776528](https://www.ncbi.nlm.nih.gov/clinvar/variation/3776528/) |

**All HGVS expressions:** `NC_000002.11:g.131350467_131350473del`, `NC_000002.12:g.130592894_130592900del`, `NG_008148.1:g.11610_11616del`, `NM_001270420.2:c.534_540del`, `NM_001270421.2:c.424_430del`, `NM_032545.4:c.649_655del`

## 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 -2.088 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.586, pLI 0.85842. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (6 of 6)** — 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** (chr2:130449946, chr2:130401552). 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 (gnomAD v4.1): grpmax **0.0148%** (amr) · FAF95 0.00401% · FAF99 0.00208% · 3/20,316 in the highest group · 3/419,862 alleles overall — ultra-rare (popmax 0.0148%, amr).

*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}

**CFC1** population constraint: LOEUF 0.586, pLI 0.85842, missense-Z 1.748; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 64.18, 24% of residues very-high.

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

*Describes the biological roles of CFC1 (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:** CFC1's established molecular role includes nodal binding.


### Pathways affected {#pathways}

CFC1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of signaling by NODAL](https://reactome.org/content/detail/R-HSA-1433617) | electronic |
| [Signaling by NODAL](https://reactome.org/content/detail/R-HSA-1181150) | electronic |

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

**Molecular function:** nodal binding.

**Biological process:** nodal signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-01 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related CFC1 variant pages (same residue, condition, or type): [CFC1 p.Ala175fs](/variant/cfc1-p-ala175fs), [CFC1 p.Arg87fs](/variant/cfc1-p-arg87fs), [CFC1 p.Lys30fs](/variant/cfc1-p-lys30fs).

### 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 3776528). 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.*