# NM_020975.6(RET):c.1038C>T (p.Phe346=)

https://sugi.bio/variant/ret-p-phe346

## Summary

**RET p.Phe346= (c.1038C>T)** is classified **Benign/Likely benign** in RET (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-22). Ultra-rare (popmax 0.0165%, mid); Associated with hereditary neoplastic syndrome.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs1240935395 · 3 submitters · 3 linked conditions · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the RET gene that is classified as benign/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.Phe346= |
| Coding change (HGVS c.) | c.1038C>T |
| MANE Select transcript | [NM_020975](https://www.ncbi.nlm.nih.gov/nuccore/NM_020975) |
| dbSNP | [rs1240935395](https://www.ncbi.nlm.nih.gov/snp/rs1240935395/) |
| Variant type | single nucleotide variant |
| Location | chr10:43106546-43106546 (GRCh38) |
| ClinVar | [VCV706913](https://www.ncbi.nlm.nih.gov/clinvar/variation/706913/) |

**All HGVS expressions:** `LRG_518:g.34478C>T`, `LRG_518t1:c.1038C>T`, `LRG_518t2:c.1038C>T`, `NC_000010.10:g.43601994C>T`, `NC_000010.11:g.43106546C>T`, `NG_007489.1:g.34478C>T`, `NM_000323.2:c.1038C>T`, `NM_001355216.2:c.276C>T`, `NM_001406743.1:c.1038C>T`, `NM_001406744.1:c.1038C>T`, `NM_001406759.1:c.1038C>T`, `NM_001406760.1:c.1038C>T`, `NM_001406761.1:c.909C>T`, `NM_001406762.1:c.909C>T`, `NM_001406763.1:c.1038C>T`, `NM_001406764.1:c.909C>T`, `NM_001406765.1:c.1038C>T`, `NM_001406766.1:c.750C>T`, `NM_001406767.1:c.750C>T`, `NM_001406768.1:c.909C>T`, `NM_001406769.1:c.867+1353C>T`, `NM_001406770.1:c.750C>T`, `NM_001406771.1:c.626-2485C>T`, `NM_001406772.1:c.867+1353C>T`, `NM_001406773.1:c.626-2485C>T`, `NM_001406774.1:c.738+1353C>T`, `NM_001406775.1:c.338-2485C>T`, `NM_001406776.1:c.338-2485C>T`, `NM_001406777.1:c.338-2485C>T`, `NM_001406778.1:c.338-2485C>T`, `NM_001406779.1:c.625+3917C>T`, `NM_001406780.1:c.625+3917C>T`, `NM_001406781.1:c.625+3917C>T`, `NM_001406782.1:c.625+3917C>T`, `NM_001406783.1:c.496+3917C>T`, `NM_001406784.1:c.74-2485C>T`, `NM_001406785.1:c.625+3917C>T`, `NM_001406786.1:c.496+3917C>T`, `NM_001406787.1:c.625+3917C>T`, `NM_001406788.1:c.338-5553C>T`, `NM_001406789.1:c.338-5553C>T`, `NM_001406790.1:c.338-5553C>T`, `NM_001406791.1:c.338-5553C>T`, `NM_001406792.1:c.74-5553C>T`, `NM_001406793.1:c.74-5553C>T`, `NM_001406794.1:c.74-5553C>T`, `NM_020629.2:c.1038C>T`, `NM_020630.7:c.1038C>T`, `NM_020975.6:c.1038C>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 (below), not from a missing predictor score.
- Conservation: phyloP -4.595, GERP -3.36 — fast-evolving / accelerated position
- CADD: **PHRED 9.125**. 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 (C>G, Δ0.71 donor 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 (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.000292% · FAF99 0.000211% · 1/6,076 in the highest group · 11/1,613,518 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,076 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,440 |
| African / African-American | 0.00134% | 74,876 |
| European (non-Finnish) | 0.000678% | 147,473 |

*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}

Residue **346** lies in the 'cadherin-like region 3 (cld3)' region.

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. p.Phe346= falls in the cadherin-like region 3 (cld3) region.


### 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-22.

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

**Submission history:** 3 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-11-10 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2025-02-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-22 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [multiple endocrine neoplasia type 2A](https://sugi.bio/atlas/disease/multiple-endocrine-neoplasia-type-2a/), [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, Multiple endocrine neoplasia type 2A, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, Tumor predisposition, Hereditary neoplastic syndrome, MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA, PTC SYNDROME, SIPPLE SYNDROME.

## Similar variants {#similar}

Related RET variant pages (same residue, condition, or type): [RET p.Phe346Cys](/variant/ret-p-phe346cys), [RET p.Phe346Leu](/variant/ret-p-phe346leu), [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 2026-10-14); 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 706913). 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.*