Is RET p.Asp489Val (c.1466A>T) pathogenic?

RET p.Asp489Val (c.1466A>T) is classified Uncertain significance in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-02). AlphaMissense: ambiguous (0.3479); Absent from gnomAD v4.1; Associated with multiple endocrine neoplasia type 2A.

What condition is associated with RET p.Asp489Val (c.1466A>T)?

RET p.Asp489Val (c.1466A>T) is associated with multiple endocrine neoplasia type 2A (ClinVar).

How common is RET p.Asp489Val (c.1466A>T) in the general population?

RET p.Asp489Val (c.1466A>T) is absent from gnomAD v4.1 (gnomAD).

How is Multiple endocrine neoplasia type 2 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RET p.Asp489Val (c.1466A>T)?

AlphaMissense predicts ambiguous (score 0.3479) — an in-silico prediction, not a clinical call.

RET p.Asp489Val

c.1466A>T · rs923351888 · VCV584748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3479 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

multiple endocrine neoplasia type 2A

Computational evidence

Protein change
AlphaMissense	0.3479	ambiguous
REVEL	0.426	indeterminate
SaProt	LLR -7.33	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 0.096, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	18.12	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

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.Asp489Val
Coding: c.1466A>T
MANE Select: NM_020975
dbSNP: rs923351888
Type: single nucleotide variant
Location: chr10:43111409 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 489: the 'cadherin-like region 4 (cld4)' region; a UniProt-annotated variant site (in)

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

Disease context

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

For Multiple endocrine neoplasia type 2 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

RET p.Asp489Asn Benign/Likely benign ★★ same residue
RET p.Asp489= Likely benign ★★ same residue
RET p.Asp489Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
RET p.Asp489Gly Uncertain significance ★ same residue
RET p.Asp631Tyr Pathogenic ★★ ⚠ same condition
RET p.Cys609Gly Pathogenic ★★ same condition
RET p.Cys609Ser Pathogenic ★★ same condition
RET p.Cys609Tyr 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-asp489val (accessed [today's date]).

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