# NM_001145252.3(CFP):c.1208G>A (p.Arg403His)

https://sugi.bio/variant/cfp-p-arg403his

## Summary

**CFP p.Arg403His (c.1208G>A)** is classified **Uncertain significance** in CFP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-27). AlphaMissense: likely benign (0.3065); Very rare (popmax 0.00376%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00376%, sas)

## For patients & families {#patients}

This is a change in the CFP 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 | [CFP](https://sugi.bio/atlas/gene/CFP/) |
| Protein change (HGVS p.) | p.Arg403His |
| Coding change (HGVS c.) | c.1208G>A |
| MANE Select transcript | [NM_001145252](https://www.ncbi.nlm.nih.gov/nuccore/NM_001145252) |
| Variant type | single nucleotide variant |
| Location | chrX:47626094-47626094 (GRCh38) |
| ClinVar | [VCV4768473](https://www.ncbi.nlm.nih.gov/clinvar/variation/4768473/) |

**All HGVS expressions:** `LRG_129:g.9212G>A`, `LRG_129t1:c.1208G>A`, `NC_000023.10:g.47485493C>T`, `NC_000023.11:g.47626094C>T`, `NG_009893.1:g.9212G>A`, `NM_001145252.3:c.1208G>A`, `NM_002621.2:c.1208G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.3065)
- REVEL 0.79 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -11.427 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 5.922, GERP 1.72, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.4**. 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 0.79** across the covering region of the MANE Select transcript (47,624,278–47,629,844), spanning 5,566 bp. Chi-square p 3.9e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.35 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00376%** (sas) · FAF95 0.000623% · FAF99 0.000233% · 2/53,237 in the highest group · 6/1,176,277 alleles overall — very rare (popmax 0.00376%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00376% | 26,618 |
| East Asian | 0.00312% | 32,010 |
| Admixed American | 0.00247% | 40,426 |
| European (non-Finnish) | 0.000228% | 438,806 |

*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.*

## Protein context {#protein}

Residue **403** lies in a β-strand; a disulfide bond; the tsp type-1 6 domain.

AlphaFold model confidence (whole protein): pLDDT 83.75, 56% of residues very-high.

**14 experimental structure(s)** (PDB): [1W0R](https://www.rcsb.org/structure/1W0R), [1W0S](https://www.rcsb.org/structure/1W0S), [6RUR](https://www.rcsb.org/structure/6RUR), [6RUS](https://www.rcsb.org/structure/6RUS), [6RUV](https://www.rcsb.org/structure/6RUV), [6RV6](https://www.rcsb.org/structure/6RV6).

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

*Describes the biological roles of CFP (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:** p.Arg403His falls in the tsp type-1 6 domain. In Reactome, CFP is annotated in disease pathway(s) including **Defective B3GALTL causes PpS**.

**Disease mechanism (Reactome):** CFP loss or alteration is curated in [Defective B3GALTL causes PpS](https://reactome.org/content/detail/R-HSA-5083635).

### Pathways affected {#pathways}

CFP participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective B3GALTL causes PpS](https://reactome.org/content/detail/R-HSA-5083635) | curated |
| [Activation of C3 and C5](https://reactome.org/content/detail/R-HSA-174577) | curated |
| [Alternative complement activation](https://reactome.org/content/detail/R-HSA-173736) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [O-glycosylation of TSR domain-containing proteins](https://reactome.org/content/detail/R-HSA-5173214) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |

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

**Biological process:** positive regulation of complement activation, alternative pathway, protein stabilization.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-27.

**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 | 2025-07-27 |

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

## Similar variants {#similar}

Related CFP variant pages (same residue, condition, or type): [CFP p.Arg403Cys](/variant/cfp-p-arg403cys), [CFP p.Trp321Gly](/variant/cfp-p-trp321gly), [CFP p.Ala402Gly](/variant/cfp-p-ala402gly), [CFP p.Arg157Gln](/variant/cfp-p-arg157gln), [CFP p.Arg157Trp](/variant/cfp-p-arg157trp), [CFP p.Arg159Cys](/variant/cfp-p-arg159cys), [CFP p.Arg247Trp](/variant/cfp-p-arg247trp), [CFP p.Arg438Trp](/variant/cfp-p-arg438trp).

### 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 4768473). 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.*