Is RET p.Cys609Phe (c.1826G>T) pathogenic?

RET p.Cys609Phe (c.1826G>T) is classified Pathogenic in RET (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-24). AlphaMissense: likely pathogenic (0.9698); Very rare (popmax 0.00017%, nfe); Associated with RET-related disorder.

What condition is associated with RET p.Cys609Phe (c.1826G>T)?

RET p.Cys609Phe (c.1826G>T) is associated with RET-related disorder, hereditary neoplastic syndrome, multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Cys609Phe (c.1826G>T) in the general population?

RET p.Cys609Phe (c.1826G>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about RET p.Cys609Phe (c.1826G>T)?

AlphaMissense predicts likely pathogenic (score 0.9698) — an in-silico prediction, not a clinical call.

RET p.Cys609Phe

c.1826G>T · rs77939446 · VCV38284

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9698 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RET-related disorder

Computational evidence

Protein change
AlphaMissense	0.9698	likely pathogenic ✓ concordant with ClinVar · top 4% in RET
REVEL	0.942	strongly pathogenic-leaning
SaProt	LLR -10.10	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	25.7	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

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,832 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,460,994 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: RET
Protein: p.Cys609Phe
Coding: c.1826G>T
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

RET-related disorder

Also linked: hereditary neoplastic syndrome multiple endocrine neoplasia type 2

Similar variants

RET p.Cys609Arg Pathogenic ★★ same residue
RET p.Cys609Gly Pathogenic ★★ same residue
RET p.Cys609Ser 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-cys609phe (accessed [today's date]).

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