Is RET p.Val804Leu (c.2410G>T) pathogenic?

RET p.Val804Leu (c.2410G>T) is classified Pathogenic in RET (ClinVar, Multiple submitters, 20 submitters; last evaluated 2025-11-05). AlphaMissense: likely pathogenic (0.5946); Very rare (popmax 0.00136%, nfe); Associated with RET-related disorder.

What condition is associated with RET p.Val804Leu (c.2410G>T)?

RET p.Val804Leu (c.2410G>T) is associated with RET-related disorder, Hirschsprung disease, susceptibility to, 1, familial medullary thyroid carcinoma (ClinVar).

How common is RET p.Val804Leu (c.2410G>T) in the general population?

RET p.Val804Leu (c.2410G>T) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about RET p.Val804Leu (c.2410G>T)?

AlphaMissense predicts likely pathogenic (score 0.5946) — an in-silico prediction, not a clinical call.

RET p.Val804Leu

c.2410G>T · rs79658334 · VCV13946

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 20 submitters

AlphaMissense

likely pathogenic

0.5946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RET-related disorder

Computational evidence

Protein change
AlphaMissense	0.5946	likely pathogenic ✓ concordant with ClinVar
REVEL	0.715	pathogenic-leaning
SaProt	LLR -8.34	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	26.8	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 0.00136% European (non-Finnish) · 16/1,177,970 alleles

Filtering AF 0.000804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000651%

Overall 0.00131% 21/1,605,504 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0102%	9,822
Finnishnot grpmax-eligible	0.00164%	60,942
European (non-Finnish)grpmax	0.00136%	73,623
South Asian	0.00111%	90,322

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val804Leu
Coding: c.2410G>T
MANE Select: NM_020975
dbSNP: rs79658334
Type: single nucleotide variant
Location: chr10:43119548 (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

RET-related disorder

Also linked: Hirschsprung disease, susceptibility to, 1 familial medullary thyroid carcinoma multiple endocrine neoplasia type 2B pheochromocytoma multiple endocrine neoplasia type 2A hereditary neoplastic syndrome multiple endocrine neoplasia multiple endocrine neoplasia type 2

Similar variants

RET p.Val804Met Pathogenic/Likely pathogenic ★★ ⚠ same residue
RET p.Val804Ala Uncertain significance ★★ ⚠ same residue
RET p.Val804= 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
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-val804leu (accessed [today's date]).

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