Is RET p.Arg587Trp (c.1759C>T) pathogenic?

RET p.Arg587Trp (c.1759C>T) is classified Uncertain significance in RET (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.1249); Very rare (popmax 0.00534%, afr); Associated with multiple endocrine neoplasia type 2B.

What condition is associated with RET p.Arg587Trp (c.1759C>T)?

RET p.Arg587Trp (c.1759C>T) is associated with multiple endocrine neoplasia type 2B, Hirschsprung disease, susceptibility to, 1, familial medullary thyroid carcinoma (ClinVar).

How common is RET p.Arg587Trp (c.1759C>T) in the general population?

RET p.Arg587Trp (c.1759C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about RET p.Arg587Trp (c.1759C>T)?

AlphaMissense predicts likely benign (score 0.1249) — an in-silico prediction, not a clinical call.

RET p.Arg587Trp

c.1759C>T · rs748905470 · VCV820028

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1249 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

multiple endocrine neoplasia type 2B

Computational evidence

Protein change
AlphaMissense	0.1249	likely benign
REVEL	0.628	indeterminate
SaProt	LLR -4.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.45 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.6	GERP 0.76, phastCons 0.95
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,906 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00112% 18/1,612,656 alleles · very rare exomes 17/1,460,462 · genomes 1/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,726
South Asian	0.00329%	30,349
European (non-Finnish)	0.000933%	107,160

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.Arg587Trp
Coding: c.1759C>T
MANE Select: NM_020975
dbSNP: rs748905470
Type: single nucleotide variant
Location: chr10:43112963 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 587: a functional site (breakpoint for translocation to form the trim27/ret oncogene)

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

Disease context

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

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

Similar variants

RET p.Arg587Gly Uncertain significance ★ ⚠ same residue
RET p.Arg587= Likely benign ★ same residue
RET p.Arg587Gln 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-arg587trp (accessed [today's date]).

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