Is RET p.Leu730Val (c.2188C>G) pathogenic?

RET p.Leu730Val (c.2188C>G) is classified Uncertain significance in RET (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-16). AlphaMissense: likely benign (0.2554); Absent from gnomAD v4.1; Associated with multiple endocrine neoplasia type 2.

What condition is associated with RET p.Leu730Val (c.2188C>G)?

RET p.Leu730Val (c.2188C>G) is associated with multiple endocrine neoplasia type 2, hereditary neoplastic syndrome (ClinVar).

How common is RET p.Leu730Val (c.2188C>G) in the general population?

RET p.Leu730Val (c.2188C>G) is absent from gnomAD v4.1 (gnomAD).

How is Multiple endocrine neoplasia type 2 inherited?

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

What do computational predictors say about RET p.Leu730Val (c.2188C>G)?

AlphaMissense predicts likely benign (score 0.2554) — an in-silico prediction, not a clinical call.

RET p.Leu730Val

c.2188C>G · rs1838076782 · VCV943106

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2554 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple endocrine neoplasia type 2

Computational evidence

Protein change
AlphaMissense	0.2554	likely benign
REVEL	0.771	pathogenic-leaning
SaProt	LLR -10.92	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 1.1, phastCons 0.99
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	23.3	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.Leu730Val
Coding: c.2188C>G
MANE Select: NM_020975
dbSNP: rs1838076782
Type: single nucleotide variant
Location: chr10:43116635 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 730: a UniProt-annotated variant site (confers resistance to vandetanib, lenvatinib, cabozantinib and nintedanib inhibitors); a UniProt-annotated variant site (confers resistance to vandetanib, cabozantinib and nintedanib inhibitors); a β-strand; a binding site; the protein kinase 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

Also linked: hereditary neoplastic syndrome

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.Leu730= Likely benign ★★ same residue
RET c.1759+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET c.1879+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET p.Arg180Ter Pathogenic ★★ same condition
RET p.Arg77Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
RET p.Arg873Trp Likely pathogenic ★★ same condition
RET p.Arg897Ter Pathogenic ★★ same condition
RET p.Asp631Tyr 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-leu730val (accessed [today's date]).

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