Is RET p.Leu712Pro (c.2135T>C) pathogenic?

RET p.Leu712Pro (c.2135T>C) is classified Conflicting classifications of pathogenicity in RET (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-15). AlphaMissense: likely benign (0.0332); Very rare (popmax 0.00167%, amr); Associated with Hirschsprung disease, susceptibility to, 1.

What condition is associated with RET p.Leu712Pro (c.2135T>C)?

RET p.Leu712Pro (c.2135T>C) is associated with Hirschsprung disease, susceptibility to, 1, hereditary neoplastic syndrome, multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Leu712Pro (c.2135T>C) in the general population?

RET p.Leu712Pro (c.2135T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about RET p.Leu712Pro (c.2135T>C)?

AlphaMissense predicts likely benign (score 0.0332) — an in-silico prediction, not a clinical call.

RET p.Leu712Pro

c.2135T>C · rs760272063 · VCV405531

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0332 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hirschsprung disease, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.0332	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR 0.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	16.79	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 0.00167% Admixed American · 1/59,878 alleles

Overall 6.86e-05% 1/1,456,964 alleles · very rare

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.Leu712Pro
Coding: c.2135T>C
MANE Select: NM_020975
dbSNP: rs760272063
Type: single nucleotide variant
Location: chr10:43114735 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 712: a functional site (breakpoint for translocation to form pcm1-ret; ret-ccdc6; ret-golga5; ret-trim24 and ret-trim33 oncogenes)

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

Disease context

Hirschsprung disease, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome multiple endocrine neoplasia type 2

Similar variants

RET p.Leu712= Likely benign ★ 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.Arg897Gln Pathogenic ★★ ⚠ same condition
RET p.Arg897Ter 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-leu712pro (accessed [today's date]).

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