Is RET p.Arg112fs (c.335del) pathogenic?

RET p.Arg112fs (c.335del) is classified Likely pathogenic in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-09). Associated with Hirschsprung disease, susceptibility to, 1.

What condition is associated with RET p.Arg112fs (c.335del)?

RET p.Arg112fs (c.335del) is associated with Hirschsprung disease, susceptibility to, 1 (ClinVar).

RET p.Arg112fs

c.335del · VCV4852792

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

Hirschsprung disease, susceptibility to, 1

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 2 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.7	GERP 0.6, phastCons 0.92

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

Variant & gene context

Gene: RET
Protein: p.Arg112fs
Coding: c.335del
MANE Select: NM_020975
Type: Deletion
Location: chr10:43100720 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 112: the 'cadherin-like region 1 (cld1)' region

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

Disease context

Hirschsprung disease, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RET p.Arg112Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
RET p.Arg112His Conflicting classifications of pathogenicity ★ ⚠ same residue
RET p.Arg112Leu Uncertain significance ★★ ⚠ same residue
RET p.Ile927fs Likely pathogenic ★ same condition
RET p.Arg112= Conflicting classifications of pathogenicity ★ same residue
RET p.Arg112Gly Uncertain significance ★ ⚠ same residue
RET c.1879+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET p.Arg180Ter 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-arg112fs (accessed [today's date]).

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