# NM_020975.6(RET):c.1665C>T (p.Phe555=)

https://sugi.bio/variant/ret-p-phe555

## Summary

**RET p.Phe555= (c.1665C>T)** is classified **Likely benign** in RET (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-14). Very rare (popmax 0.000169%, nfe); Associated with hereditary neoplastic syndrome.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs761815073 · 3 submitters · 2 linked conditions · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the RET gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, 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.Phe555= |
| Coding change (HGVS c.) | c.1665C>T |
| MANE Select transcript | [NM_020975](https://www.ncbi.nlm.nih.gov/nuccore/NM_020975) |
| dbSNP | [rs761815073](https://www.ncbi.nlm.nih.gov/snp/rs761815073/) |
| Variant type | single nucleotide variant |
| Location | chr10:43112869-43112869 (GRCh38) |
| ClinVar | [VCV543784](https://www.ncbi.nlm.nih.gov/clinvar/variation/543784/) |

**All HGVS expressions:** `LRG_518:g.40801C>T`, `LRG_518t1:c.1665C>T`, `LRG_518t2:c.1665C>T`, `NC_000010.10:g.43608317C>T`, `NC_000010.11:g.43112869C>T`, `NG_007489.1:g.40801C>T`, `NM_000323.2:c.1665C>T`, `NM_001355216.2:c.903C>T`, `NM_001406743.1:c.1665C>T`, `NM_001406744.1:c.1665C>T`, `NM_001406759.1:c.1665C>T`, `NM_001406760.1:c.1665C>T`, `NM_001406761.1:c.1536C>T`, `NM_001406762.1:c.1536C>T`, `NM_001406763.1:c.1665C>T`, `NM_001406764.1:c.1536C>T`, `NM_001406765.1:c.1665C>T`, `NM_001406766.1:c.1377C>T`, `NM_001406767.1:c.1377C>T`, `NM_001406768.1:c.1536C>T`, `NM_001406769.1:c.1269C>T`, `NM_001406770.1:c.1377C>T`, `NM_001406771.1:c.1227C>T`, `NM_001406772.1:c.1269C>T`, `NM_001406773.1:c.1227C>T`, `NM_001406774.1:c.1140C>T`, `NM_001406775.1:c.939C>T`, `NM_001406776.1:c.939C>T`, `NM_001406777.1:c.939C>T`, `NM_001406778.1:c.939C>T`, `NM_001406779.1:c.768C>T`, `NM_001406780.1:c.768C>T`, `NM_001406781.1:c.768C>T`, `NM_001406782.1:c.768C>T`, `NM_001406783.1:c.639C>T`, `NM_001406784.1:c.675C>T`, `NM_001406785.1:c.768C>T`, `NM_001406786.1:c.639C>T`, `NM_001406787.1:c.768C>T`, `NM_001406788.1:c.480C>T`, `NM_001406789.1:c.480C>T`, `NM_001406790.1:c.480C>T`, `NM_001406791.1:c.480C>T`, `NM_001406792.1:c.216C>T`, `NM_001406793.1:c.216C>T`, `NM_001406794.1:c.216C>T`, `NM_020629.2:c.1665C>T`, `NM_020630.7:c.1665C>T`, `NM_020975.6:c.1665C>T`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 2.659, GERP 0.936, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 16.18**. 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 deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.20**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,966 in the highest group · 2/1,614,048 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}

**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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-14.

**Submitter consensus:** conflicting (2 Likely benign, 1 Likely Benign).

**Submission history:** 3 submissions (2019–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2023-09-05 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-06-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-14 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [multiple endocrine neoplasia type 2](https://sugi.bio/atlas/disease/multiple-endocrine-neoplasia-type-2/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Multiple endocrine neoplasia, type 2, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, Tumor predisposition, Hereditary neoplastic syndrome.

## Same-residue context {#hotspot}

Residue **555** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [RET p.Phe555Cys](/variant/ret-p-phe555cys). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related RET variant pages (same residue, condition, or type): [RET p.Phe555Cys](/variant/ret-p-phe555cys), [RET p.Phe555Tyr](/variant/ret-p-phe555tyr), [RET c.1759+1G>A](/variant/ret-c-1759-plus-1g-a), [RET c.1879+1G>A](/variant/ret-c-1879-plus-1g-a), [RET p.Arg180Ter](/variant/ret-p-arg180ter), [RET p.Arg77Cys](/variant/ret-p-arg77cys), [RET p.Arg873Trp](/variant/ret-p-arg873trp), [RET p.Arg897Ter](/variant/ret-p-arg897ter).

### 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 543784). 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.*