# NM_000492.4(CFTR):c.1920T>C (p.Phe640=)

https://sugi.bio/variant/cftr-p-phe640

## Summary

**CFTR p.Phe640= (c.1920T>C)** is classified **Conflicting classifications of pathogenicity** in CFTR (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-01-29). Rare (popmax 0.127%, amr); Associated with congenital bilateral aplasia of vas deferens from CFTR mutation.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs145877746 · 13 submitters · 3 linked conditions · rare (popmax 0.127%, amr)

## For patients & families {#patients}

This is a change in the CFTR gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 13 submitters, and is linked to congenital bilateral aplasia of vas deferens from CFTR mutation.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015243/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.Phe640= |
| Coding change (HGVS c.) | c.1920T>C |
| MANE Select transcript | [NM_000492](https://www.ncbi.nlm.nih.gov/nuccore/NM_000492) |
| dbSNP | [rs145877746](https://www.ncbi.nlm.nih.gov/snp/rs145877746/) |
| Variant type | single nucleotide variant |
| Location | chr7:117592087-117592087 (GRCh38) |
| ClinVar | [VCV256250](https://www.ncbi.nlm.nih.gov/clinvar/variation/256250/) |

**All HGVS expressions:** `LRG_663:g.131304T>C`, `LRG_663t1:c.1920T>C`, `NC_000007.13:g.117232141T>C`, `NC_000007.14:g.117592087T>C`, `NG_016465.4:g.131304T>C`, `NM_000492.4:c.1920T>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 0.39, GERP -2.89, phastCons 0.996 — weakly conserved position
- CADD: **PHRED 12.06**. 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 **0.127%** (amr) · FAF95 0.104% · FAF99 0.0953% · 76/59,970 in the highest group · 103/1,613,558 alleles overall — rare (popmax 0.127%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.127% | 789 |
| Remaining individuals (not grpmax-eligible) | 0.032% | 3,124 |
| African / African-American | 0.00533% | 18,759 |
| European (non-Finnish) | 0.000254% | 393,261 |

*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 **640** lies in a UniProt-annotated variant site (in cf); the abc transporter 1 domain; an α-helix.

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.Phe640= 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-29.

**Submitter consensus:** conflicting (10 Likely benign, 2 Benign, 2 Uncertain significance).

**Submission history:** 14 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2018-02-21 |
| Natera, Inc. | Likely benign | no assertion criteria provided | clinical testing | 2018-04-05 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2014-11-07 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-02-06 |
| Genome-Nilou Lab | Likely benign | criteria provided, single submitter | clinical testing | 2021-07-22 |
| Genome-Nilou Lab | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-22 |
| PreventionGenetics, part of Exact Sciences | Likely benign | criteria provided, single submitter | clinical testing |  |
| Johns Hopkins Genomics, Johns Hopkins University | Likely benign | criteria provided, single submitter | clinical testing | 2020-06-11 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Likely benign | criteria provided, single submitter | clinical testing | 2021-01-12 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-04 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-03-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-29 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-10-24 |

## Associated conditions {#conditions}

[congenital bilateral aplasia of vas deferens from CFTR mutation](https://sugi.bio/atlas/disease/congenital-bilateral-aplasia-of-vas-deferens-from-cftr-mutation/), [cystic fibrosis](https://sugi.bio/atlas/disease/cystic-fibrosis/), [CFTR-related disorder](https://sugi.bio/atlas/disease/cftr-related-disorder/).

**Reported phenotype names (ClinVar):** Congenital bilateral aplasia of vas deferens from CFTR mutation, not specified, not provided, Cystic fibrosis, CFTR-related disorder, CFTR-related disorders, CFTR-related condition, AllHighlyPenetrant, none provided, MUCOVISCIDOSIS.

## Similar variants {#similar}

Related CFTR variant pages (same residue, condition, or type): [CFTR p.Phe640Leu](/variant/cftr-p-phe640leu), [CFTR p.Phe640Cys](/variant/cftr-p-phe640cys), [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 256250). 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.*