Is RET p.Cys620Phe (c.1859G>T) pathogenic?

RET p.Cys620Phe (c.1859G>T) is classified Pathogenic in RET (ClinVar, Multiple submitters, 17 submitters; last evaluated 2025-10-13). AlphaMissense: likely pathogenic (0.9608); Absent from gnomAD v4.1; Associated with familial medullary thyroid carcinoma.

What condition is associated with RET p.Cys620Phe (c.1859G>T)?

RET p.Cys620Phe (c.1859G>T) is associated with familial medullary thyroid carcinoma, Hirschsprung disease, susceptibility to, 1, multiple endocrine neoplasia type 2B (ClinVar).

How common is RET p.Cys620Phe (c.1859G>T) in the general population?

RET p.Cys620Phe (c.1859G>T) is absent from gnomAD v4.1 (gnomAD).

How is Isolated familial medullary thyroid carcinoma inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RET p.Cys620Phe (c.1859G>T)?

AlphaMissense predicts likely pathogenic (score 0.9608) — an in-silico prediction, not a clinical call.

RET p.Cys620Phe

c.1859G>T · rs77503355 · VCV13928

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 17 submitters

AlphaMissense

likely pathogenic

0.9608 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial medullary thyroid carcinoma

Computational evidence

Protein change
AlphaMissense	0.9608	likely pathogenic ✓ concordant with ClinVar · top 5% in RET
REVEL	0.969	strongly pathogenic-leaning
SaProt	LLR -10.83	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RET
Protein: p.Cys620Phe
Coding: c.1859G>T
MANE Select: NM_020975
dbSNP: rs77503355
Type: single nucleotide variant
Location: chr10:43113655 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 620: a UniProt-annotated variant site (in men2a and mtc; familial form); a UniProt-annotated variant site (in men2a and mtc; familial and sporadic forms); a UniProt-annotated variant site (in men2a, mtc and hscr1; familial and sporadic forms); a UniProt-annotated variant site (in men2a and hscr1); a UniProt-annotated variant site (in men2a); a disulfide bond

Full RET gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial medullary thyroid carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Hirschsprung disease, susceptibility to, 1 multiple endocrine neoplasia type 2B pheochromocytoma multiple endocrine neoplasia type 2A hereditary neoplastic syndrome multiple endocrine neoplasia type 2

For Isolated familial medullary thyroid carcinoma (Orphanet):

Inheritance: Autosomal dominant

Similar variants

RET p.Cys620Arg Pathogenic ★★ same residue
RET p.Cys620Gly Pathogenic ★★ same residue
RET p.Cys620Ser Pathogenic ★★ same residue
RET p.Cys620Trp Pathogenic ★★ same residue
RET p.Cys620Tyr Pathogenic ★★ same residue
RET p.Cys620= Conflicting classifications of pathogenicity ★ same residue
RET p.Cys620Ter Pathogenic ★ same residue
RET c.1759+1G>A Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ret-p-cys620phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown