Is RET p.Val282Ala (c.845T>C) pathogenic?

RET p.Val282Ala (c.845T>C) is classified Uncertain significance in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-07). AlphaMissense: likely benign (0.1231); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Val282Ala (c.845T>C)?

RET p.Val282Ala (c.845T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is RET p.Val282Ala (c.845T>C) in the general population?

RET p.Val282Ala (c.845T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about RET p.Val282Ala (c.845T>C)?

AlphaMissense predicts likely benign (score 0.1231) — an in-silico prediction, not a clinical call.

RET p.Val282Ala

c.845T>C · VCV3432305

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1231 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1231	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -7.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.45 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.3	GERP 0.043, phastCons 0.17
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	22.7	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 8.48e-05% European (non-Finnish) · 1/1,179,820 alleles

Overall 6.85e-05% 1/1,460,674 alleles · very rare

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.Val282Ala
Coding: c.845T>C
MANE Select: NM_020975
Type: single nucleotide variant
Location: chr10:43105171 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 282: the 'cadherin-like region 3 (cld3)' region

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

Similar variants

RET p.Val282Met Uncertain significance ★★ ⚠ same residue
RET p.Val282= Likely benign ★★ same residue
RET p.Val282Gly Uncertain significance ★ ⚠ same residue
RET p.Val282fs Pathogenic ★ same residue
RET p.Val282Leu Uncertain significance ★ ⚠ same residue
RET c.1759+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET p.Arg873Trp Likely pathogenic ★★ same condition
RET p.Asp631Tyr 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-val282ala (accessed [today's date]).

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