Is RET p.Val804= (c.2412G>A) pathogenic?

RET p.Val804= (c.2412G>A) is classified Conflicting classifications of pathogenicity in RET (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-12-18). Very rare (popmax 8.49e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Val804= (c.2412G>A)?

RET p.Val804= (c.2412G>A) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Val804= (c.2412G>A) in the general population?

RET p.Val804= (c.2412G>A) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

RET p.Val804=

c.2412G>A · rs767045208 · VCV1034965

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.28	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 5.8	GERP 0.82, phastCons 1
Overall
CADD	15.75	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,178,360 alleles

Overall 0.000657% 1/152,166 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.Val804=
Coding: c.2412G>A
MANE Select: NM_020975
dbSNP: rs767045208
Type: single nucleotide variant
Location: chr10:43119550 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 804: a UniProt-annotated variant site (in mtc; familial form; confers resistance to vandetanib, lenvatinib, cabozantinib and nintedanib inhibitors); a UniProt-annotated variant site (in mtc; familial form; faster autophosphorylation and activation, leading to enhanced activity; confers resistance to vandetanib, lenvatinib, cabozantinib and nintedanib inhibitors); a β-strand; the protein kinase domain

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 2

Similar variants

RET p.Val804Leu Pathogenic ★★ ⚠ same residue
RET p.Val804Met Pathogenic/Likely pathogenic ★★ ⚠ same residue
RET p.Val804Ala Uncertain significance ★★ ⚠ 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

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-val804 (accessed [today's date]).

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