# NM_020975.6(RET):c.2001_2003inv (p.Pro668Val)

https://sugi.bio/variant/ret-p-pro668val

## Summary

**RET p.Pro668Val (c.2001_2003inv)** is classified **Uncertain significance** in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-08). Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the RET gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to hereditary neoplastic syndrome.

*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 | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RET](https://sugi.bio/atlas/gene/RET/) |
| Protein change (HGVS p.) | p.Pro668Val |
| Coding change (HGVS c.) | c.2001_2003inv |
| MANE Select transcript | [NM_020975](https://www.ncbi.nlm.nih.gov/nuccore/NM_020975) |
| Variant type | Inversion |
| Location | chr10:43114601-43114603 (GRCh38) |
| ClinVar | [VCV4844014](https://www.ncbi.nlm.nih.gov/clinvar/variation/4844014/) |

**All HGVS expressions:** `LRG_518:g.42533_42535inv`, `LRG_518t1:c.2001_2003invACC`, `LRG_518t2:c.2001_2003invACC`, `NC_000010.10:g.43610049_43610051inv`, `NC_000010.11:g.43114601_43114603inv`, `NG_007489.1:g.42533_42535inv`, `NM_001355216.2:c.1239_1241inv`, `NM_001406743.1:c.2001_2003inv`, `NM_001406744.1:c.2001_2003inv`, `NM_001406759.1:c.2001_2003inv`, `NM_001406760.1:c.2001_2003inv`, `NM_001406761.1:c.1872_1874inv`, `NM_001406762.1:c.1872_1874inv`, `NM_001406763.1:c.1880-14_1880-12inv`, `NM_001406764.1:c.1872_1874inv`, `NM_001406765.1:c.1880-14_1880-12inv`, `NM_001406766.1:c.1713_1715inv`, `NM_001406767.1:c.1713_1715inv`, `NM_001406768.1:c.1751-14_1751-12inv`, `NM_001406769.1:c.1605_1607inv`, `NM_001406770.1:c.1713_1715inv`, `NM_001406771.1:c.1563_1565inv`, `NM_001406772.1:c.1605_1607inv`, `NM_001406773.1:c.1563_1565inv`, `NM_001406774.1:c.1476_1478inv`, `NM_001406775.1:c.1275_1277inv`, `NM_001406776.1:c.1275_1277inv`, `NM_001406777.1:c.1275_1277inv`, `NM_001406778.1:c.1275_1277inv`, `NM_001406779.1:c.1104_1106inv`, `NM_001406780.1:c.1104_1106inv`, `NM_001406781.1:c.1104_1106inv`, `NM_001406782.1:c.1104_1106inv`, `NM_001406783.1:c.975_977inv`, `NM_001406784.1:c.1011_1013inv`, `NM_001406785.1:c.984_986inv`, `NM_001406786.1:c.975_977inv`, `NM_001406787.1:c.983-14_983-12inv`, `NM_001406788.1:c.816_818inv`, `NM_001406789.1:c.816_818inv`, `NM_001406790.1:c.816_818inv`, `NM_001406791.1:c.696_698inv`, `NM_001406792.1:c.552_554inv`, `NM_001406793.1:c.552_554inv`, `NM_001406794.1:c.552_554inv`, `NM_020630.7:c.2001_2003inv`, `NM_020975.4:c.2001_2003delACCinsGGT`, `NM_020975.6:c.2001_2003inv`

## 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 -7.431, GERP -3.73 — fast-evolving / accelerated position
- Regional missense constraint: **o/e 0.88** across the covering region of the MANE Select transcript (43,102,441–43,119,709), spanning 17,268 bp. Chi-square p 0.00012. 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 inversion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**RET** population constraint: LOEUF 0.24, pLI 1, missense-Z 2.6933; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **multiple endocrine neoplasia type 2B** — Definitive (AD)
- **multiple endocrine neoplasia type 2A** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 79.27, 52% of residues very-high.

**34 experimental structure(s)** (PDB): [2IVS](https://www.rcsb.org/structure/2IVS), [2IVT](https://www.rcsb.org/structure/2IVT), [2IVU](https://www.rcsb.org/structure/2IVU), [2IVV](https://www.rcsb.org/structure/2IVV), [2X2K](https://www.rcsb.org/structure/2X2K), [2X2L](https://www.rcsb.org/structure/2X2L) — incl. mutant structure 6NE7.

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

*Describes the biological roles of RET (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:** RET's established molecular role includes transmembrane receptor protein tyrosine kinase activity.


### Pathways affected {#pathways}

RET participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [NPAS4 regulates expression of target genes](https://reactome.org/content/detail/R-HSA-9768919) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [RET signaling](https://reactome.org/content/detail/R-HSA-8853659) | curated |
| [Formation of the nephric duct](https://reactome.org/content/detail/R-HSA-9830364) | electronic |
| [Formation of the ureteric bud](https://reactome.org/content/detail/R-HSA-9830674) | electronic |

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

**Molecular function:** transmembrane receptor protein tyrosine kinase activity, calcium ion binding.

**Biological process:** neuron cell-cell adhesion, positive regulation of neuron projection development, regulation of cell adhesion, positive regulation of cell migration, membrane protein proteolysis, positive regulation of cell adhesion mediated by integrin.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-08.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-08 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome.

## Similar variants {#similar}

Related RET variant pages (same residue, condition, or type): [RET p.Pro668Leu](/variant/ret-p-pro668leu), [RET p.Pro668Ala](/variant/ret-p-pro668ala), [RET p.Pro668Ser](/variant/ret-p-pro668ser), [RET p.Pro668=](/variant/ret-p-pro668), [RET p.Tyr1062Ile](/variant/ret-p-tyr1062ile), [RET c.1759+1G>A](/variant/ret-c-1759-plus-1g-a), [RET c.1760-2_1760-1del](/variant/ret-c-1760-minus-2-1760-minus-1del), [RET p.Ala883Phe](/variant/ret-p-ala883phe).

### 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 4844014). 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.*