Is RET p.Leu769= (c.2307G>T) pathogenic?

RET p.Leu769= (c.2307G>T) is classified Benign in RET (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). Common (popmax 88.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with pheochromocytoma.

What condition is associated with RET p.Leu769= (c.2307G>T)?

RET p.Leu769= (c.2307G>T) is associated with pheochromocytoma, multiple endocrine neoplasia type 2B, multiple endocrine neoplasia type 2A (ClinVar).

RET p.Leu769=

Q: How common is RET p.Leu769= (c.2307G>T) in the general population?

RET p.Leu769= (c.2307G>T) is common (popmax 88.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2307G>T · rs1800861 · VCV167590

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 88.3%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

pheochromocytoma

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 0.32	GERP -1.9, phastCons 0.6
Overall
CADD	4.881	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 88.3% African / African-American · 66,208/74,994 alleles

Filtering AF 87.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 87.5%

Overall 75.8% 1,222,984/1,613,240 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	88.3%	1
Amishnot grpmax-eligible	82.2%	1
European (non-Finnish)	77%	1
Admixed American	76.8%	1
Finnishnot grpmax-eligible	76.5%	1
Remaining individualsnot grpmax-eligible	74.6%	1
Middle Eastern	71.7%	1
Ashkenazi Jewishnot grpmax-eligible	71.4%	1
South Asian	64.5%	2
East Asian	48.6%	2

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.Leu769=
Coding: c.2307G>T
MANE Select: NM_020975
dbSNP: rs1800861
Type: single nucleotide variant
Location: chr10:43118395 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 769: an α-helix; the protein kinase domain

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

Disease context

pheochromocytoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple endocrine neoplasia type 2B multiple endocrine neoplasia type 2A hereditary neoplastic syndrome multiple endocrine neoplasia type 2

Similar variants

RET p.Leu769Phe 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
RET p.Arg897Ter Pathogenic ★★ same condition
RET p.Asp631Tyr 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-leu769 (accessed [today's date]).

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