Is RET p.Pro684Leu (c.2051C>T) pathogenic?

RET p.Pro684Leu (c.2051C>T) is classified Uncertain significance in RET (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-07). AlphaMissense: likely benign (0.2484); Very rare (popmax 0.00333%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Pro684Leu (c.2051C>T)?

RET p.Pro684Leu (c.2051C>T) is associated with hereditary neoplastic syndrome, Hirschsprung disease, susceptibility to, 1, multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Pro684Leu (c.2051C>T) in the general population?

RET p.Pro684Leu (c.2051C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about RET p.Pro684Leu (c.2051C>T)?

AlphaMissense predicts likely benign (score 0.2484) — an in-silico prediction, not a clinical call.

RET p.Pro684Leu

c.2051C>T · rs760088950 · VCV820592

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2484 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2484	likely benign
REVEL	0.674	pathogenic-leaning
SaProt	LLR -6.14	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.22 · evaluated, not missing
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	26.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,996 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000496% 8/1,612,886 alleles · very rare exomes 7/1,460,762 · genomes 1/152,124 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,998
East Asian	0.00223%	44,860
Remaining individualsnot grpmax-eligible	0.0016%	62,474
African / African-American	0.00133%	74,920
South Asian	0.0011%	91,076
European (non-Finnish)	0.000169%	590,005

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.Pro684Leu
Coding: c.2051C>T
MANE Select: NM_020975
dbSNP: rs760088950
Type: single nucleotide variant
Location: chr10:43114651 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Hirschsprung disease, susceptibility to, 1 multiple endocrine neoplasia type 2

Similar variants

RET p.Pro684Ser 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-pro684leu (accessed [today's date]).

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