# NM_000492.4(CFTR):c.2028T>C (p.Pro676=)

https://sugi.bio/variant/cftr-p-pro676

## Summary

**CFTR p.Pro676= (c.2028T>C)** is classified **Likely benign** in CFTR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-12). Very rare (popmax 0.000169%, nfe); Associated with cystic fibrosis.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs751504707 · 2 submitters · 1 linked condition · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the CFTR gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to cystic fibrosis.

*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 recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 1441 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CFTR is a diagnostic-grade gene on 9 Genomics England panels |

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

- Exocrine pancreatic insufficiency — Very frequent (99-80%)
- Malabsorption — Very frequent (99-80%)
- Bronchiectasis — Very frequent (99-80%)
- Recurrent respiratory infections — Very frequent (99-80%)
- Airway obstruction — Very frequent (99-80%)
- Elevated sweat chloride — Very frequent (99-80%)
- Absent vas deferens — Very frequent (99-80%)
- Failure to thrive — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006233/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CFTR](https://sugi.bio/atlas/gene/CFTR/) |
| Protein change (HGVS p.) | p.Pro676= |
| Coding change (HGVS c.) | c.2028T>C |
| MANE Select transcript | [NM_000492](https://www.ncbi.nlm.nih.gov/nuccore/NM_000492) |
| dbSNP | [rs751504707](https://www.ncbi.nlm.nih.gov/snp/rs751504707/) |
| Variant type | single nucleotide variant |
| Location | chr7:117592195-117592195 (GRCh38) |
| ClinVar | [VCV755642](https://www.ncbi.nlm.nih.gov/clinvar/variation/755642/) |

**All HGVS expressions:** `LRG_663:g.131412T>C`, `LRG_663t1:c.2028T>C`, `NC_000007.13:g.117232249T>C`, `NC_000007.14:g.117592195T>C`, `NG_016465.4:g.131412T>C`, `NM_000492.4:c.2028T>C`

## 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 -0.533, GERP -0.815 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.724**. 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** — 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 **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,970 in the highest group · 2/1,613,780 alleles overall — very rare (popmax 0.000169%, nfe).

*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}

**CFTR** population constraint: LOEUF 1.152, pLI 2.3757e-39, missense-Z -1.0736; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/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):

- **cystic fibrosis** — Definitive (AR)

## Protein context {#protein}

Residue **676** lies in a UniProt-annotated variant site (in cf); the 'disordered r region' region.

AlphaFold model confidence (whole protein): pLDDT 75.96, 33% of residues very-high.

**60 experimental structure(s)** (PDB): [1XMI](https://www.rcsb.org/structure/1XMI), [1XMJ](https://www.rcsb.org/structure/1XMJ), [2BBO](https://www.rcsb.org/structure/2BBO), [2BBS](https://www.rcsb.org/structure/2BBS), [2BBT](https://www.rcsb.org/structure/2BBT), [2LOB](https://www.rcsb.org/structure/2LOB).

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

*Describes the biological roles of CFTR (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:** CFTR's established molecular role includes chloride channel activity. p.Pro676= falls in the disordered r region region. In Reactome, CFTR is annotated in disease pathway(s) including **Defective CFTR causes cystic fibrosis**.

**Disease mechanism (Reactome):** CFTR loss or alteration is curated in [Defective CFTR causes cystic fibrosis](https://reactome.org/content/detail/R-HSA-5678895).

### Pathways affected {#pathways}

CFTR participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective CFTR causes cystic fibrosis](https://reactome.org/content/detail/R-HSA-5678895) | curated |
| [ABC-family protein mediated transport](https://reactome.org/content/detail/R-HSA-382556) | curated |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [Developmental Lineage of Pancreatic Ductal Cells](https://reactome.org/content/detail/R-HSA-9925563) | curated |
| [RHO GTPases regulate CFTR trafficking](https://reactome.org/content/detail/R-HSA-5627083) | curated |
| [RHOQ GTPase cycle](https://reactome.org/content/detail/R-HSA-9013406) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |
| [Aggrephagy](https://reactome.org/content/detail/R-HSA-9646399) | electronic |
| [Chaperone Mediated Autophagy](https://reactome.org/content/detail/R-HSA-9613829) | electronic |
| [Late endosomal microautophagy](https://reactome.org/content/detail/R-HSA-9615710) | electronic |

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

**Molecular function:** chloride channel activity, intracellularly ATP-gated chloride channel activity, bicarbonate transmembrane transporter activity, ATP hydrolysis activity, chloride channel inhibitor activity, enzyme binding.

**Biological process:** bicarbonate transport, response to endoplasmic reticulum stress, transepithelial water transport, multicellular organismal-level water homeostasis, chloride transmembrane transport, cellular response to forskolin.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-05-12.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2020–2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-11-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-05-12 |

## Associated conditions {#conditions}

[cystic fibrosis](https://sugi.bio/atlas/disease/cystic-fibrosis/).

**Reported phenotype names (ClinVar):** Cystic fibrosis, MUCOVISCIDOSIS.

## Similar variants {#similar}

Related CFTR variant pages (same residue, condition, or type): [CFTR p.Pro676Ala](/variant/cftr-p-pro676ala), [CFTR p.Pro676Ser](/variant/cftr-p-pro676ser), [CFTR c.1585-1G>A](/variant/cftr-c-1585-minus-1g-a), [CFTR c.1766+1G>A](/variant/cftr-c-1766-plus-1g-a), [CFTR c.2657+5G>A](/variant/cftr-c-2657-plus-5g-a), [CFTR c.2988+1G>A](/variant/cftr-c-2988-plus-1g-a), [CFTR c.3718-2477C>T](/variant/cftr-c-3718-minus-2477c-t), [CFTR c.489+1G>T](/variant/cftr-c-489-plus-1g-t).

### 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 755642). 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.*