Is RET p.Pro537= (c.1611A>G) pathogenic?

RET p.Pro537= (c.1611A>G) is classified Likely benign in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). Very rare (popmax 0.0019%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Pro537= (c.1611A>G)?

RET p.Pro537= (c.1611A>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is RET p.Pro537= (c.1611A>G) in the general population?

RET p.Pro537= (c.1611A>G) is very rare (popmax 0.0019%, amr) (gnomAD).

RET p.Pro537=

c.1611A>G · rs2132800619 · VCV1776392

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0019%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.15	GERP -4.2
Overall
CADD	1.978	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0019% Admixed American · 1/52,768 alleles

Overall 6.39e-05% 1/1,564,814 alleles · very rare exomes 1/1,412,512 · genomes 0/152,302 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: RET
Protein: p.Pro537=
Coding: c.1611A>G
MANE Select: NM_020975
dbSNP: rs2132800619
Type: single nucleotide variant
Location: chr10:43112187 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RET p.Pro537Gln Uncertain significance ★★ ⚠ same residue
RET p.Pro537Ser Uncertain significance ★★ ⚠ same residue
RET p.Pro537Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
RET c.1759+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET p.Arg873Trp Likely pathogenic ★★ same condition
RET p.Asp631Tyr Pathogenic ★★ ⚠ same condition
RET p.Cys609Arg Pathogenic ★★ same condition
RET p.Cys609Gly 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-pro537 (accessed [today's date]).

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