Is RET p.Pro766= (c.2298G>A) pathogenic?

RET p.Pro766= (c.2298G>A) is classified Conflicting classifications of pathogenicity in RET (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0143%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Pro766= (c.2298G>A)?

RET p.Pro766= (c.2298G>A) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 2B, multiple endocrine neoplasia type 2A (ClinVar).

How common is RET p.Pro766= (c.2298G>A) in the general population?

RET p.Pro766= (c.2298G>A) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

RET p.Pro766=

c.2298G>A · rs140658743 · VCV220687

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Conditions

hereditary neoplastic syndrome

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 -0.41	GERP -3.7
Overall
CADD	7.877	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0143% South Asian · 13/91,080 alleles

Filtering AF 0.00844% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.00551% 89/1,613,860 alleles · ultra-rare exomes 83/1,461,664 · genomes 6/152,196 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	7,006
European (non-Finnish)	0.00559%	17,878
African / African-American	0.00534%	18,732
Remaining individualsnot grpmax-eligible	0.0048%	20,823
East Asian	0.00446%	22,442
Admixed American	0.00167%	60,000

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.Pro766=
Coding: c.2298G>A
MANE Select: NM_020975
dbSNP: rs140658743
Type: single nucleotide variant
Location: chr10:43118386 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 766: an α-helix; the protein kinase domain

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

Also linked: multiple endocrine neoplasia type 2B multiple endocrine neoplasia type 2A multiple endocrine neoplasia type 2

Similar variants

RET p.Pro766Arg Uncertain significance ★★ ⚠ same residue
RET p.Pro766Leu Uncertain significance ★★ ⚠ same residue
RET p.Pro766Gln Uncertain significance ★ ⚠ 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
RET p.Arg873Trp 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-pro766 (accessed [today's date]).

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