Is RET p.Cys620Ter (c.1860C>A) pathogenic?

RET p.Cys620Ter (c.1860C>A) is classified Pathogenic in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2015-07-30). Absent from gnomAD v4.1; Associated with Hirschsprung disease.

What condition is associated with RET p.Cys620Ter (c.1860C>A)?

RET p.Cys620Ter (c.1860C>A) is associated with Hirschsprung disease (ClinVar).

How common is RET p.Cys620Ter (c.1860C>A) in the general population?

RET p.Cys620Ter (c.1860C>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.Cys620Ter

c.1860C>A · rs79890926 · VCV3076011

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

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 10 of 20
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.8	GERP -3.4
Overall
CADD	29.0	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.Cys620Ter
Coding: c.1860C>A
MANE Select: NM_020975
dbSNP: rs79890926
Type: single nucleotide variant
Location: chr10:43113656 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 620: a UniProt-annotated variant site (in men2a and mtc; familial form); a UniProt-annotated variant site (in men2a and mtc; familial and sporadic forms); a UniProt-annotated variant site (in men2a, mtc and hscr1; familial and sporadic forms); a UniProt-annotated variant site (in men2a and hscr1); a UniProt-annotated variant site (in men2a); a disulfide bond

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.Cys620Arg Pathogenic ★★ same residue
RET p.Cys620Gly Pathogenic ★★ same residue
RET p.Cys620Tyr Pathogenic ★★ same residue
RET p.Cys620Phe Pathogenic ★★ same residue
RET p.Cys620Ser Pathogenic ★★ same residue
RET p.Cys620Trp Pathogenic ★★ same residue
RET p.Cys620= Conflicting classifications of pathogenicity ★ same residue
RET p.Cys609Arg 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-cys620ter (accessed [today's date]).

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