Is RET p.Pro218= (c.654G>A) pathogenic?

RET p.Pro218= (c.654G>A) is classified Benign/Likely benign in RET (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-28). Rare (popmax 0.45%, afr); Associated with multiple endocrine neoplasia.

What condition is associated with RET p.Pro218= (c.654G>A)?

RET p.Pro218= (c.654G>A) is associated with multiple endocrine neoplasia, Hirschsprung disease, susceptibility to, 1, pheochromocytoma (ClinVar).

How common is RET p.Pro218= (c.654G>A) in the general population?

RET p.Pro218= (c.654G>A) is rare (popmax 0.45%, afr) (gnomAD).

RET p.Pro218=

c.654G>A · rs137928436 · VCV220254

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

rare (popmax 0.45%, afr)

Conditions

multiple endocrine neoplasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP -4.2
Overall
CADD	6.449	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.45% African / African-American · 336/74,658 alleles

Filtering AF 0.41% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.395%

Overall 0.0234% 369/1,578,406 alleles · rare exomes 186/1,426,082 · genomes 183/152,324 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.45%	222
Admixed American	0.0303%	3,303
Remaining individualsnot grpmax-eligible	0.0228%	4,390
South Asian	0.00114%	87,782
European (non-Finnish)	8.55e-05%	1,169,827

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.Pro218=
Coding: c.654G>A
MANE Select: NM_020975
dbSNP: rs137928436
Type: single nucleotide variant
Location: chr10:43104980 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 218: the cadherin domain

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

Disease context

multiple endocrine neoplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Hirschsprung disease, susceptibility to, 1 pheochromocytoma hereditary neoplastic syndrome multiple endocrine neoplasia type 2 renal hypodysplasia/aplasia 1

Similar variants

RET p.Pro218Ala Uncertain significance ★★ ⚠ same residue
RET p.Pro218Arg Uncertain significance ★★ ⚠ same residue
RET p.Pro218Ser Uncertain significance ★★ ⚠ same residue
RET p.Pro218Leu Likely benign ★ same residue
RET c.1759+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET c.1879+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET p.Arg180Ter Pathogenic ★★ same condition
RET p.Arg77Cys Pathogenic/Likely 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-pro218 (accessed [today's date]).

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