Is RET p.Val804Met (c.2410G>A) pathogenic?

RET p.Val804Met (c.2410G>A) is classified Pathogenic/Likely pathogenic in RET (ClinVar, Multiple submitters, 51 submitters; last evaluated 2026-05-01). AlphaMissense: ambiguous (0.3831); Ultra-rare (popmax 0.0185%, amr); Associated with Inherited phaeochromocytoma and paraganglioma excluding NF1.

What condition is associated with RET p.Val804Met (c.2410G>A)?

RET p.Val804Met (c.2410G>A) is associated with Inherited phaeochromocytoma and paraganglioma excluding NF1, Hirschsprung disease, susceptibility to, 1, familial medullary thyroid carcinoma (ClinVar).

How common is RET p.Val804Met (c.2410G>A) in the general population?

RET p.Val804Met (c.2410G>A) is ultra-rare (popmax 0.0185%, amr) (gnomAD).

What do computational predictors say about RET p.Val804Met (c.2410G>A)?

AlphaMissense predicts ambiguous (score 0.3831) — an in-silico prediction, not a clinical call.

RET p.Val804Met

c.2410G>A · rs79658334 · VCV37102

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 51 submitters

AlphaMissense

ambiguous

0.3831 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0185%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inherited phaeochromocytoma and paraganglioma excluding NF1

Computational evidence

Protein change
AlphaMissense	0.3831	ambiguous
REVEL	0.716	pathogenic-leaning
SaProt	LLR -8.68	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
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	29.0	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 0.0185% Admixed American · 11/59,440 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00996%

Overall 0.0122% 196/1,605,504 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0185%	5,404
Remaining individualsnot grpmax-eligible	0.0145%	6,900
South Asian	0.0133%	7,527
European (non-Finnish)	0.0122%	8,180
Finnishnot grpmax-eligible	0.0115%	8,706
East Asian	0.0112%	8,914
African / African-American	0.00937%	10,671
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,466

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.Val804Met
Coding: c.2410G>A
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

Inherited phaeochromocytoma and paraganglioma excluding NF1

Also linked: Hirschsprung disease, susceptibility to, 1 familial medullary thyroid carcinoma multiple endocrine neoplasia type 2B ovarian cancer pheochromocytoma multiple endocrine neoplasia type 2A hereditary neoplastic syndrome multiple endocrine neoplasia type 2 renal hypodysplasia/aplasia 1 central hypoventilation syndrome, congenital

Similar variants

RET p.Val804Leu 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-val804met (accessed [today's date]).

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