Is RET p.Ser224Ter (c.668_669dup) pathogenic?

RET p.Ser224Ter (c.668669dup) is classified Pathogenic in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-06). Associated with multiple endocrine neoplasia type 2.

What condition is associated with RET p.Ser224Ter (c.668_669dup)?

RET p.Ser224Ter (c.668_669dup) is associated with multiple endocrine neoplasia type 2 (ClinVar).

How is Multiple endocrine neoplasia type 2 inherited?

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

RET p.Ser224Ter

c.668_669dup · VCV3644687

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

Conditions

multiple endocrine neoplasia type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 4 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.6	GERP -0.22, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: RET
Protein: p.Ser224Ter
Coding: c.668_669dup
MANE Select: NM_020975
Type: Duplication
Location: chr10:43104992 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 224: a β-strand; a disulfide bond; the cadherin domain

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

Disease context

multiple endocrine neoplasia type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple endocrine neoplasia type 2 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

RET p.Ser224Cys Uncertain significance ★ ⚠ same residue
RET p.Ser224Thr Uncertain significance ★ ⚠ same residue
RET p.Ser224= Likely benign ★ same residue
RET p.Pro956fs Pathogenic ★★ same condition
RET c.3027_3039+19dup Uncertain significance ★★ same condition
RET p.Arg177_Glu178insIleArg Uncertain significance ★★ same condition
RET p.Cys630_Asp631insProLeuCys Uncertain significance ★★ same condition
RET p.Leu17_Leu18insArgLeuLeuLeuLeuLeu Uncertain significance ★★ 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-ser224ter (accessed [today's date]).

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