Is RET p.Pro684Ser (c.2050C>T) pathogenic?

RET p.Pro684Ser (c.2050C>T) is classified Uncertain significance in RET (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-14). AlphaMissense: likely benign (0.1968); Very rare (popmax 0.00167%, amr); Associated with multiple endocrine neoplasia type 2.

What condition is associated with RET p.Pro684Ser (c.2050C>T)?

RET p.Pro684Ser (c.2050C>T) is associated with multiple endocrine neoplasia type 2, Hirschsprung disease, susceptibility to, 1, familial medullary thyroid carcinoma (ClinVar).

How common is RET p.Pro684Ser (c.2050C>T) in the general population?

RET p.Pro684Ser (c.2050C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Multiple endocrine neoplasia type 2 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RET p.Pro684Ser (c.2050C>T)?

AlphaMissense predicts likely benign (score 0.1968) — an in-silico prediction, not a clinical call.

RET p.Pro684Ser

c.2050C>T · rs141347316 · VCV299896

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1968 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

multiple endocrine neoplasia type 2

Computational evidence

Protein change
AlphaMissense	0.1968	likely benign
REVEL	0.491	indeterminate
SaProt	LLR -5.35	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,010 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,613,046 alleles · very rare exomes 7/1,460,830 · genomes 0/152,216 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,010
European (non-Finnish)	0.000508%	196,668

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.Pro684Ser
Coding: c.2050C>T
MANE Select: NM_020975
dbSNP: rs141347316
Type: single nucleotide variant
Location: chr10:43114650 (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

multiple endocrine neoplasia type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Hirschsprung disease, susceptibility to, 1 familial medullary thyroid carcinoma multiple endocrine neoplasia type 2B pheochromocytoma multiple endocrine neoplasia type 2A hereditary neoplastic syndrome multiple endocrine neoplasia renal hypodysplasia/aplasia 1

For Multiple endocrine neoplasia type 2 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

RET p.Pro684Leu Uncertain significance ★★ ⚠ same residue
RET p.Pro684= Conflicting classifications of pathogenicity ★ same residue
RET p.Pro684Arg Uncertain significance ★ ⚠ same residue
RET p.Pro684Gln 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

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-pro684ser (accessed [today's date]).

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