Is RET p.Trp1069Arg (c.3205T>C) pathogenic?

RET p.Trp1069Arg (c.3205T>C) is classified Uncertain significance in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-01). AlphaMissense: likely pathogenic (0.8218); Very rare (popmax 0.000254%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Trp1069Arg (c.3205T>C)?

RET p.Trp1069Arg (c.3205T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is RET p.Trp1069Arg (c.3205T>C) in the general population?

RET p.Trp1069Arg (c.3205T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about RET p.Trp1069Arg (c.3205T>C)?

AlphaMissense predicts likely pathogenic (score 0.8218) — an in-silico prediction, not a clinical call.

RET p.Trp1069Arg

c.3205T>C · rs1432376339 · VCV2568374

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8218 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8218	likely pathogenic
REVEL	0.767	pathogenic-leaning
SaProt	LLR -4.21	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 4,468 bp · p 0.69 · regional, not allelic
Overall
CADD	27.3	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,034 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,194 alleles · very rare exomes 3/1,461,868 · genomes 0/152,326 · joint denominator

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.Trp1069Arg
Coding: c.3205T>C
MANE Select: NM_020975
dbSNP: rs1432376339
Type: single nucleotide variant
Location: chr10:43128129 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB

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.Trp1069Ser Uncertain significance ★★ ⚠ same residue
RET p.Trp1069Ter Uncertain significance ★★ same residue
RET p.Trp1069Cys 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
RET p.Cys609Arg Pathogenic ★★ same condition
RET p.Cys609Gly 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-trp1069arg (accessed [today's date]).

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