Is RET p.Ala883Val (c.2648C>T) pathogenic?

RET p.Ala883Val (c.2648C>T) is classified Uncertain significance in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). AlphaMissense: likely pathogenic (0.6689); Very rare (popmax 0.00167%, amr); Associated with multiple endocrine neoplasia type 2.

What condition is associated with RET p.Ala883Val (c.2648C>T)?

RET p.Ala883Val (c.2648C>T) is associated with multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Ala883Val (c.2648C>T) in the general population?

RET p.Ala883Val (c.2648C>T) is very rare (popmax 0.00167%, amr) (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.Ala883Val (c.2648C>T)?

AlphaMissense predicts likely pathogenic (score 0.6689) — an in-silico prediction, not a clinical call.

RET p.Ala883Val

c.2648C>T · rs1293645997 · VCV2893353

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6689 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple endocrine neoplasia type 2

Computational evidence

Protein change
AlphaMissense	0.6689	likely pathogenic
REVEL	0.893	moderately pathogenic-leaning
SaProt	LLR -11.45	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.44 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 4,087 bp · p 2.5e-11 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00167% Admixed American · 1/60,002 alleles

Overall 0.000274% 4/1,461,682 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,002
Finnishnot grpmax-eligible	0.00156%	64,022
South Asian	0.0011%	91,056
European (non-Finnish)	8.47e-05%	1,180,004

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.Ala883Val
Coding: c.2648C>T
MANE Select: NM_020975
dbSNP: rs1293645997
Type: single nucleotide variant
Location: chr10:43120121 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 883: a UniProt-annotated variant site (in men2b; somatic mutation in sporadic medullary thyroid carcinoma; requires 2 nucleotide substitutions); a β-strand; the protein kinase domain

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

Disease context

multiple endocrine neoplasia type 2 — 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.Ala883Pro Uncertain significance ★★ ⚠ same residue
RET p.Ala883Thr Uncertain significance ★★ ⚠ same residue
RET p.Ala883= Likely benign ★★ same residue
RET p.Ala883Phe Pathogenic/Likely pathogenic ★★ same residue
RET p.Ala883Asp Uncertain significance ★★ ⚠ same residue
RET c.1879+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET p.Arg180Ter Pathogenic ★★ same condition
RET p.Arg77Cys Pathogenic/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-ala883val (accessed [today's date]).

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