Is RET p.Ser522Ile (c.1565G>T) pathogenic?

RET p.Ser522Ile (c.1565G>T) is classified Uncertain significance in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-04). AlphaMissense: ambiguous (0.3923); No allele count reported in gnomAD v4.1 (AN 1,597,820); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Ser522Ile (c.1565G>T)?

RET p.Ser522Ile (c.1565G>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is RET p.Ser522Ile (c.1565G>T) in the general population?

RET p.Ser522Ile (c.1565G>T) is no allele count reported in gnomAD v4.1 (AN 1,597,820) (gnomAD).

What do computational predictors say about RET p.Ser522Ile (c.1565G>T)?

AlphaMissense predicts ambiguous (score 0.3923) — an in-silico prediction, not a clinical call.

RET p.Ser522Ile

c.1565G>T · VCV3788299

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3923 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,597,820)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3923	ambiguous
REVEL	0.373	indeterminate
SaProt	LLR -5.30	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -2.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	20.6	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

No allele count reported in gnomAD v4.1 (AN 1,597,820). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: RET
Protein: p.Ser522Ile
Coding: c.1565G>T
MANE Select: NM_020975
Type: single nucleotide variant
Location: chr10:43112141 (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.Ser522= Conflicting classifications of pathogenicity ★ same residue
RET p.Ser522Cys Uncertain significance ★★ same residue
RET p.Ser522Asn 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-ser522ile (accessed [today's date]).

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