Is RET p.Pro956fs (c.2865dup) pathogenic?

RET p.Pro956fs (c.2865dup) is classified Pathogenic in RET (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-09-10). Absent from gnomAD; Associated with multiple endocrine neoplasia type 2.

What condition is associated with RET p.Pro956fs (c.2865dup)?

RET p.Pro956fs (c.2865dup) is associated with multiple endocrine neoplasia type 2, Hirschsprung disease (ClinVar).

How common is RET p.Pro956fs (c.2865dup) in the general population?

RET p.Pro956fs (c.2865dup) 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.Pro956fs

c.2865dup · rs1564500612 · VCV599634

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

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.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 17 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP -0.76, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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.Pro956fs
Coding: c.2865dup
MANE Select: NM_020975
dbSNP: rs1564500612
Type: Duplication
Location: chr10:43123732 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 956: the protein kinase domain

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

Also linked: Hirschsprung disease

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.Pro956Leu Uncertain significance ★★ ⚠ same residue
RET p.Pro956Ser Uncertain significance ★ ⚠ same residue
RET c.3027_3039+19dup Uncertain significance ★★ same condition
RET p.Arg177_Glu178insIleArg Uncertain significance ★★ same condition
RET p.Cys630_Asp631insProLeuCys Uncertain significance ★★ same condition
RET p.Leu17_Leu18insArgLeuLeuLeuLeuLeu Uncertain significance ★★ same condition
RET p.Leu22_Gly23insProLeuLeu Uncertain significance ★★ same condition
RET p.Pro20_Leu21insPro 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-pro956fs (accessed [today's date]).

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