# NM_001928.4(CFD):c.441_442del (p.Cys148fs)

https://sugi.bio/variant/cfd-p-cys148fs

## Summary

**CFD p.Cys148fs (c.441_442del)** is classified **Uncertain significance** in CFD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-14). Very rare (popmax 0.00223%, eas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the CFD 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 | [CFD](https://sugi.bio/atlas/gene/CFD/) |
| Protein change (HGVS p.) | p.Cys148fs |
| Coding change (HGVS c.) | c.441_442del |
| MANE Select transcript | [NM_001928](https://www.ncbi.nlm.nih.gov/nuccore/NM_001928) |
| Variant type | Microsatellite |
| Location | chr19:861778-861779 (GRCh38) |
| ClinVar | [VCV3607721](https://www.ncbi.nlm.nih.gov/clinvar/variation/3607721/) |

**All HGVS expressions:** `LRG_46:g.7114CT[2]`, `LRG_46t1:c.437_438CT[2]`, `NC_000019.10:g.861778CT[2]`, `NC_000019.9:g.861778CT[2]`, `NG_007274.1:g.7114CT[2]`, `NM_001317335.2:c.462_463del`, `NM_001928.4:c.441_442del`

## 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 7.204, GERP 1.85, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.948, pLI 2.4289e-12. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 5**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 29.1**. 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.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 0.000292% · FAF99 0.000211% · 1/44,750 in the highest group · 9/1,605,052 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,750 |
| European (non-Finnish) | 0.000679% | 147,358 |

*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}

**CFD** population constraint: LOEUF 1.948, pLI 2.4289e-12, missense-Z -4.9554; ClinGen dosage — haploinsufficiency 30, 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}

Residue **148** lies in a disulfide bond; the peptidase s1 domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 91.19, 80% of residues very-high.

**40 experimental structure(s)** (PDB): [1BIO](https://www.rcsb.org/structure/1BIO), [1DFP](https://www.rcsb.org/structure/1DFP), [1DIC](https://www.rcsb.org/structure/1DIC), [1DST](https://www.rcsb.org/structure/1DST), [1DSU](https://www.rcsb.org/structure/1DSU), [1FDP](https://www.rcsb.org/structure/1FDP) — incl. mutant structure 1DST.

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

*Describes the biological roles of CFD (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:** CFD's established molecular role includes serine-type endopeptidase activity. p.Cys148fs falls in the peptidase s1 domain.


### Pathways affected {#pathways}

CFD participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Alternative complement activation](https://reactome.org/content/detail/R-HSA-173736) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |

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

**Molecular function:** serine-type endopeptidase activity.

**Biological process:** complement activation, alternative pathway, zymogen activation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-14.

**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 | 2024-10-14 |

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

## Same-residue context {#hotspot}

Residue **148** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CFD p.Cys148Ter](/variant/cfd-p-cys148ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CFD variant pages (same residue, condition, or type): [CFD p.Cys148Ter](/variant/cfd-p-cys148ter), [CFD p.Leu94fs](/variant/cfd-p-leu94fs).

### 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 3607721). 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.*