Is RET p.Ala55Ser (c.163G>T) pathogenic?

RET p.Ala55Ser (c.163G>T) is classified Uncertain significance in RET (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-23). AlphaMissense: likely benign (0.1442); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Ala55Ser (c.163G>T)?

RET p.Ala55Ser (c.163G>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is RET p.Ala55Ser (c.163G>T) in the general population?

RET p.Ala55Ser (c.163G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RET p.Ala55Ser (c.163G>T)?

AlphaMissense predicts likely benign (score 0.1442) — an in-silico prediction, not a clinical call.

RET p.Ala55Ser

c.163G>T · VCV3432296

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1442 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1442	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -7.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 0.58, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 1,972 bp · p 4.9e-10 · regional, not allelic
Overall
CADD	15.85	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RET
Protein: p.Ala55Ser
Coding: c.163G>T
MANE Select: NM_020975
Type: single nucleotide variant
Location: chr10:43100548 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 55: the 'cadherin-like region 1 (cld1)' 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.Ala55Val Uncertain significance ★ ⚠ same residue
RET p.Ala55= 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
RET p.Cys609Phe 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-ala55ser (accessed [today's date]).

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