Is RET p.Ile669Phe (c.2005A>T) pathogenic?

RET p.Ile669Phe (c.2005A>T) is classified Uncertain significance in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-03). AlphaMissense: likely benign (0.1545); Very rare (popmax 0.0011%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Ile669Phe (c.2005A>T)?

RET p.Ile669Phe (c.2005A>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is RET p.Ile669Phe (c.2005A>T) in the general population?

RET p.Ile669Phe (c.2005A>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about RET p.Ile669Phe (c.2005A>T)?

AlphaMissense predicts likely benign (score 0.1545) — an in-silico prediction, not a clinical call.

RET p.Ile669Phe

c.2005A>T · rs776986585 · VCV1784307

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1545 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1545	likely benign
REVEL	0.568	indeterminate
SaProt	LLR -6.08	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.95, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	19.55	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 0.0011% South Asian · 1/90,988 alleles

Overall 6.2e-05% 1/1,611,922 alleles · very rare exomes 1/1,460,908 · genomes 0/151,014 · 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.Ile669Phe
Coding: c.2005A>T
MANE Select: NM_020975
dbSNP: rs776986585
Type: single nucleotide variant
Location: chr10:43114605 (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.Ile669Thr Uncertain significance ★★ same residue
RET p.Ile669Val Conflicting classifications of pathogenicity ★ ⚠ same residue
RET p.Ile669= Likely benign ★ 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-ile669phe (accessed [today's date]).

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