Is RET p.Ala46Ser (c.135_136delinsGT) pathogenic?

RET p.Ala46Ser (c.135136delinsGT) is classified Uncertain significance in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-25). Absent from gnomAD; Associated with multiple endocrine neoplasia type 2.

What condition is associated with RET p.Ala46Ser (c.135_136delinsGT)?

RET p.Ala46Ser (c.135_136delinsGT) is associated with multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Ala46Ser (c.135_136delinsGT) in the general population?

RET p.Ala46Ser (c.135_136delinsGT) is absent from gnomAD (gnomAD).

How is Multiple endocrine neoplasia type 2 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

RET p.Ala46Ser

c.135_136delinsGT · rs2492113109 · VCV1975405

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

multiple endocrine neoplasia type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -8.6	GERP -3.4
Regional constraint	o/e 0.51	unconstrained · MANE · 1,972 bp · p 4.9e-10 · regional, not allelic

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. 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.Ala46Ser
Coding: c.135_136delinsGT
MANE Select: NM_020975
dbSNP: rs2492113109
Type: Indel
Location: chr10:43100520 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 46: the 'cadherin-like region 1 (cld1)' region

Full RET gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

multiple endocrine neoplasia type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple endocrine neoplasia type 2 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

RET p.Ala46= Likely benign ★★ same residue
RET p.Ala46Val Uncertain significance ★ ⚠ same residue
RET p.Ala883Phe Pathogenic/Likely pathogenic ★★ same condition
RET p.Cys634Leu Pathogenic/Likely pathogenic ★★ same condition
RET p.Lys666delinsAsnSer Likely pathogenic ★★ same condition
RET p.Ala692Glu Uncertain significance ★★ same condition
RET p.Glu991Arg Uncertain significance ★★ same condition
RET p.Leu769Phe Uncertain significance ★★ 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-ala46ser (accessed [today's date]).

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