# NM_020975.6(RET):c.1901G>T (p.Cys634Phe)

https://sugi.bio/variant/ret-p-cys634phe

## Summary

**RET p.Cys634Phe (c.1901G>T)** is classified **Pathogenic** in RET (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-10). AlphaMissense: likely pathogenic (0.5703); Very rare (popmax 0.00133%, afr); Associated with RET-related disorder.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs75996173 · 8 submitters · 6 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the RET gene that is considered disease-causing, submitted by 8 submitters, and is linked to RET-related disorder.

*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.*

**Support & next steps:** [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.Cys634Phe |
| Coding change (HGVS c.) | c.1901G>T |
| MANE Select transcript | [NM_020975](https://www.ncbi.nlm.nih.gov/nuccore/NM_020975) |
| dbSNP | [rs75996173](https://www.ncbi.nlm.nih.gov/snp/rs75996173/) |
| Variant type | single nucleotide variant |
| Location | chr10:43114501-43114501 (GRCh38) |
| ClinVar | [VCV13911](https://www.ncbi.nlm.nih.gov/clinvar/variation/13911/) |

**All HGVS expressions:** `LRG_518:g.42433G>T`, `LRG_518t1:c.1901G>T`, `LRG_518t2:c.1901G>T`, `NC_000010.10:g.43609949G>T`, `NC_000010.11:g.43114501G>T`, `NG_007489.1:g.42433G>T`, `NM_000323.2:c.1901G>T`, `NM_001355216.2:c.1139G>T`, `NM_001406743.1:c.1901G>T`, `NM_001406744.1:c.1901G>T`, `NM_001406759.1:c.1901G>T`, `NM_001406760.1:c.1901G>T`, `NM_001406761.1:c.1772G>T`, `NM_001406762.1:c.1772G>T`, `NM_001406764.1:c.1772G>T`, `NM_001406766.1:c.1613G>T`, `NM_001406767.1:c.1613G>T`, `NM_001406769.1:c.1505G>T`, `NM_001406770.1:c.1613G>T`, `NM_001406771.1:c.1463G>T`, `NM_001406772.1:c.1505G>T`, `NM_001406773.1:c.1463G>T`, `NM_001406774.1:c.1376G>T`, `NM_001406775.1:c.1175G>T`, `NM_001406776.1:c.1175G>T`, `NM_001406777.1:c.1175G>T`, `NM_001406778.1:c.1175G>T`, `NM_001406779.1:c.1004G>T`, `NM_001406780.1:c.1004G>T`, `NM_001406781.1:c.1004G>T`, `NM_001406782.1:c.1004G>T`, `NM_001406783.1:c.875G>T`, `NM_001406784.1:c.911G>T`, `NM_001406785.1:c.884G>T`, `NM_001406786.1:c.875G>T`, `NM_001406788.1:c.716G>T`, `NM_001406789.1:c.716G>T`, `NM_001406790.1:c.716G>T`, `NM_001406791.1:c.596G>T`, `NM_001406792.1:c.452G>T`, `NM_001406793.1:c.452G>T`, `NM_001406794.1:c.452G>T`, `NM_020629.2:c.1901G>T`, `NM_020630.7:c.1901G>T`, `NM_020975.6:c.1901G>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.5703) — concordant with the pathogenic call
- REVEL 0.91 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.954 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.785, GERP 0.661, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.1**. 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.*
- 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** — 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 **0.00133%** (afr) · 1/74,970 in the highest group · 1/1,455,706 alleles overall — very rare (popmax 0.00133%, afr).

*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, triplosensitivity 0 (0–3 scale). *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 **634** lies in a UniProt-annotated variant site (in men2a); a UniProt-annotated variant site (in men2a and pheochromocytoma); a UniProt-annotated variant site (in men2a, pheochromocytoma and mtc; familial form; also found as somatic mutation in a sporadic thyroid carcinoma); a UniProt-annotated variant site (in men2a, pheochromocytoma and mtc; familial form); a disulfide bond.

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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-10.

**Submitter consensus:** unanimous (10/10 Pathogenic).

**Submission history:** 10 submissions (2002–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, University of Leipzig Medical Center | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-10 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2002-05-09 |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2022-03-10 |
| Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-03 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-06 |
| KCCC/NGS Laboratory, Kuwait Cancer Control Center | Pathogenic | criteria provided, single submitter | clinical testing | 2023-05-31 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-06-27 |

## Associated conditions {#conditions}

[RET-related disorder](https://sugi.bio/atlas/disease/ret-related-disorder/), [familial medullary thyroid carcinoma](https://sugi.bio/atlas/disease/familial-medullary-thyroid-carcinoma/), [pheochromocytoma](https://sugi.bio/atlas/disease/pheochromocytoma/), [multiple endocrine neoplasia type 2A](https://sugi.bio/atlas/disease/multiple-endocrine-neoplasia-type-2a/), [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):** RET-related disorder, Multiple endocrine neoplasia type 2A, Familial medullary thyroid carcinoma, Pheochromocytoma, Multiple endocrine neoplasia, type 2, Hereditary cancer-predisposing syndrome, not provided, RET-related disorders, RET-related condition, RET-related disease.

## Same-residue context {#hotspot}

Residue **634** carries **8 other pathogenic ClinVar variants** — a recurrently-mutated position: [RET p.Cys634Gly](/variant/ret-p-cys634gly), [RET p.Cys634Tyr](/variant/ret-p-cys634tyr), [RET p.Cys634Ser](/variant/ret-p-cys634ser), [RET p.Cys634Arg](/variant/ret-p-cys634arg), [RET p.Cys634Trp](/variant/ret-p-cys634trp), [RET p.Cys634_Arg635insHisGluLeuCys](/variant/ret-p-cys634-arg635inshisgluleucys), [RET p.Cys634_Arg635delinsTrpGly](/variant/ret-p-cys634-arg635delinstrpgly), [RET p.Cys634Leu](/variant/ret-p-cys634leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related RET variant pages (same residue, condition, or type): [RET p.Cys634Arg](/variant/ret-p-cys634arg), [RET p.Cys634Gly](/variant/ret-p-cys634gly), [RET p.Cys634Ser](/variant/ret-p-cys634ser), [RET p.Cys634Trp](/variant/ret-p-cys634trp), [RET p.Cys634Tyr](/variant/ret-p-cys634tyr), [RET p.Cys634Leu](/variant/ret-p-cys634leu), [RET p.Cys634_Arg635delinsTrpGly](/variant/ret-p-cys634-arg635delinstrpgly), [RET c.1759+1G>A](/variant/ret-c-1759-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 13911). 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.*