# NM_001928.4(CFD):c.678_679delinsAA (p.Arg227Ser)

https://sugi.bio/variant/cfd-p-arg227ser

## Summary

**CFD p.Arg227Ser (c.678_679delinsAA)** is classified **Uncertain significance** in CFD (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-22). No gnomAD frequency available for this variant.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2145167344 · 1 submitter · no gnomAD frequency available for this variant

## 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.Arg227Ser |
| Coding change (HGVS c.) | c.678_679delinsAA |
| MANE Select transcript | [NM_001928](https://www.ncbi.nlm.nih.gov/nuccore/NM_001928) |
| dbSNP | [rs2145167344](https://www.ncbi.nlm.nih.gov/snp/rs2145167344/) |
| Variant type | Indel |
| Location | chr19:863154-863155 (GRCh38) |
| ClinVar | [VCV1376442](https://www.ncbi.nlm.nih.gov/clinvar/variation/1376442/) |

**All HGVS expressions:** `LRG_46:g.8490_8491delinsAA`, `NC_000019.10:g.863154_863155delinsAA`, `NC_000019.9:g.863154_863155delinsAA`, `NG_007274.1:g.8490_8491delinsAA`, `NM_001317335.2:c.699_700delinsAA`, `NM_001928.4:c.678_679delinsAA`

## 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 -2.162, GERP -5.27 — fast-evolving / accelerated position
- Regional missense constraint: **o/e 1.40** across the covering region of the MANE Select transcript (859,690–863,235), spanning 3,545 bp. Chi-square p 9.1e-15. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel 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}

**CFD** population constraint: LOEUF 1.948, pLI 2.4289e-12, missense-Z -4.9554; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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 **227** lies in the peptidase s1 domain; the 'self-inhibitor loop' region; 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.Arg227Ser 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 2021-11-22.

**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 | 2021-11-22 |

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

## Similar variants {#similar}

Related CFD variant pages (same residue, condition, or type): [CFD p.Arg227=](/variant/cfd-p-arg227), [CFD c.358-259_461delinsCATTGA](/variant/cfd-c-358-minus-259-461delinscattga), [CFD p.Ser3Ile](/variant/cfd-p-ser3ile).

### 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 1376442). 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.*