# NM_000492.4(CFTR):c.1467A>C (p.Ser489=)

https://sugi.bio/variant/cftr-p-ser489

## Summary

**CFTR p.Ser489= (c.1467A>C)** is classified **Likely benign** in CFTR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-15). No allele count reported in gnomAD v4.1 (AN 1,611,910); Associated with cystic fibrosis.

**At a glance:** Likely benign · review: Single submitter · rsID rs1799419729 · 1 submitter · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 1,611,910)

## For patients & families {#patients}

This is a change in the CFTR gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, 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.Ser489= |
| Coding change (HGVS c.) | c.1467A>C |
| MANE Select transcript | [NM_000492](https://www.ncbi.nlm.nih.gov/nuccore/NM_000492) |
| dbSNP | [rs1799419729](https://www.ncbi.nlm.nih.gov/snp/rs1799419729/) |
| Variant type | single nucleotide variant |
| Location | chr7:117559538-117559538 (GRCh38) |
| ClinVar | [VCV3231828](https://www.ncbi.nlm.nih.gov/clinvar/variation/3231828/) |

**All HGVS expressions:** `LRG_663:g.98755A>C`, `LRG_663t1:c.1467A>C`, `NC_000007.13:g.117199592A>C`, `NC_000007.14:g.117559538A>C`, `NG_016465.4:g.98755A>C`, `NM_000492.4:c.1467A>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 0.124, GERP -3.47, phastCons 0.19 — weakly conserved position
- CADD: **PHRED 5.856**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.29 acceptor gain), 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: **no allele count reported in gnomAD v4.1 (AN 1,611,910)** — 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}

**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 **489** lies in a UniProt-annotated variant site (in cf); the abc transporter 1 domain; a β-strand.

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.Ser489= falls in the abc transporter 1 domain. 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-15.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-10-15 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **489** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [CFTR p.Ser489fs](/variant/cftr-p-ser489fs), [CFTR p.Ser489Ter](/variant/cftr-p-ser489ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CFTR variant pages (same residue, condition, or type): [CFTR p.Ser489Ter](/variant/cftr-p-ser489ter), [CFTR p.Ser489fs](/variant/cftr-p-ser489fs), [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 2026-10-14); 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 3231828). 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.*