Is RET p.Trp37Ter (c.111G>A) pathogenic?

RET p.Trp37Ter (c.111G>A) is classified Pathogenic in RET (ClinVar, No assertion criteria, 1 submitter; last evaluated 2013-01-01). Absent from gnomAD v4.1; Associated with Hirschsprung disease.

What condition is associated with RET p.Trp37Ter (c.111G>A)?

RET p.Trp37Ter (c.111G>A) is associated with Hirschsprung disease (ClinVar).

How common is RET p.Trp37Ter (c.111G>A) in the general population?

RET p.Trp37Ter (c.111G>A) is absent from gnomAD v4.1 (gnomAD).

How is Hirschsprung disease inherited?

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

RET p.Trp37Ter

c.111G>A · rs1564489315 · VCV599630

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Hirschsprung disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 2 of 20
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 0.58, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

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

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.Trp37Ter
Coding: c.111G>A
MANE Select: NM_020975
dbSNP: rs1564489315
Type: single nucleotide variant
Location: chr10:43100496 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 37: a β-strand; 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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hirschsprung disease (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Multigenic/multifactorial
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

RET p.Trp37Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
RET p.Cys609Arg Pathogenic ★★ same condition
RET p.Cys611Arg Pathogenic/Likely pathogenic ★★ same condition
RET p.Cys620Arg Pathogenic ★★ same condition
RET p.Cys620Gly Pathogenic ★★ same condition
RET p.Cys620Tyr Pathogenic ★★ same condition
RET p.Ser32Leu Likely pathogenic ★★ ⚠ same condition
RET p.Arg813Trp 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-trp37ter (accessed [today's date]).

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