Is RET p.Pro841= (c.2523G>T) pathogenic?

RET p.Pro841= (c.2523G>T) is classified Conflicting classifications of pathogenicity in RET (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-04-01). Ultra-rare (popmax 0.033%, mid); Associated with multiple endocrine neoplasia.

What condition is associated with RET p.Pro841= (c.2523G>T)?

RET p.Pro841= (c.2523G>T) is associated with multiple endocrine neoplasia, Hirschsprung disease, susceptibility to, 1, pheochromocytoma (ClinVar).

How common is RET p.Pro841= (c.2523G>T) in the general population?

RET p.Pro841= (c.2523G>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

RET p.Pro841=

c.2523G>T · rs56195026 · VCV184140

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 0.033%, mid)

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 -11	GERP -4
Overall
CADD	0.033	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,056 alleles

Filtering AF 0.0198% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.019%

Overall 0.0176% 284/1,613,338 alleles · ultra-rare exomes 267/1,461,018 · genomes 17/152,320 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,028
European (non-Finnish)	0.022%	4,538
Admixed American	0.02%	5,002
Remaining individualsnot grpmax-eligible	0.0144%	6,944
African / African-American	0.00133%	75,048

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.Pro841=
Coding: c.2523G>T
MANE Select: NM_020975
dbSNP: rs56195026
Type: single nucleotide variant
Location: chr10:43119661 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 841: the protein kinase 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 multiple endocrine neoplasia type 2A hereditary neoplastic syndrome multiple endocrine neoplasia type 2 renal hypodysplasia/aplasia 1

Similar variants

RET p.Pro841Gln Uncertain significance ★★ ⚠ same residue
RET p.Pro841Ser Uncertain significance ★★ ⚠ same residue
RET p.Pro841Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro841 (accessed [today's date]).

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