Is RET p.Cys609Ser (c.1826G>C) pathogenic?

RET p.Cys609Ser (c.1826G>C) is classified Pathogenic in RET (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-28). AlphaMissense: likely pathogenic (0.987); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Cys609Ser (c.1826G>C)?

RET p.Cys609Ser (c.1826G>C) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Cys609Ser (c.1826G>C) in the general population?

RET p.Cys609Ser (c.1826G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RET p.Cys609Ser (c.1826G>C)?

AlphaMissense predicts likely pathogenic (score 0.987) — an in-silico prediction, not a clinical call.

RET p.Cys609Ser

c.1826G>C · rs77939446 · VCV1372611

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.987 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.987	likely pathogenic ✓ concordant with ClinVar · top 1% in RET
REVEL	0.963	strongly pathogenic-leaning
SaProt	LLR -11.64	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	25.4	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.Cys609Ser
Coding: c.1826G>C
MANE Select: NM_020975
dbSNP: rs77939446
Type: single nucleotide variant
Location: chr10:43113622 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 609: a UniProt-annotated variant site (in men2a); a UniProt-annotated variant site (in hscr1; familial form); a UniProt-annotated variant site (in mtc, men2a and hscr1; familial and sporadic forms); a disulfide bond

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple endocrine neoplasia type 2A multiple endocrine neoplasia type 2

Similar variants

RET p.Cys609Arg Pathogenic ★★ same residue
RET p.Cys609Gly Pathogenic ★★ same residue
RET p.Cys609Phe Pathogenic ★★ same residue
RET p.Cys609Trp Pathogenic/Likely pathogenic ★★ same residue
RET p.Cys609Tyr Pathogenic ★★ same residue
RET p.Cys609= Conflicting classifications of pathogenicity ★ same residue
RET c.1759+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET c.1879+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-cys609ser (accessed [today's date]).

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