Is RET p.Asp460Tyr (c.1378G>T) pathogenic?

RET p.Asp460Tyr (c.1378G>T) is classified Uncertain significance in RET (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-29). AlphaMissense: likely benign (0.2609); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Asp460Tyr (c.1378G>T)?

RET p.Asp460Tyr (c.1378G>T) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Asp460Tyr (c.1378G>T) in the general population?

RET p.Asp460Tyr (c.1378G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RET p.Asp460Tyr (c.1378G>T)?

AlphaMissense predicts likely benign (score 0.2609) — an in-silico prediction, not a clinical call.

RET p.Asp460Tyr

c.1378G>T · rs1085307787 · VCV426763

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2609 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2609	likely benign
REVEL	0.27	benign-leaning
SaProt	LLR -6.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 2.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	24.2	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

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.Asp460Tyr
Coding: c.1378G>T
MANE Select: NM_020975
dbSNP: rs1085307787
Type: single nucleotide variant
Location: chr10:43111321 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 460: the 'cadherin-like region 4 (cld4)' region; a disulfide bond

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.Asp460= Likely benign ★★ same residue
RET p.Asp460Glu 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
RET p.Arg897Ter 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-asp460tyr (accessed [today's date]).

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