Is RET p.Pro399Leu (c.1196C>T) pathogenic?

RET p.Pro399Leu (c.1196C>T) is classified Conflicting classifications of pathogenicity in RET (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-03-12). AlphaMissense: likely benign (0.3374); Very rare (popmax 8.47e-05%, nfe); Associated with RET-related disorder.

What condition is associated with RET p.Pro399Leu (c.1196C>T)?

RET p.Pro399Leu (c.1196C>T) is associated with RET-related disorder, Hirschsprung disease, susceptibility to, 1, hereditary neoplastic syndrome (ClinVar).

How common is RET p.Pro399Leu (c.1196C>T) in the general population?

RET p.Pro399Leu (c.1196C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about RET p.Pro399Leu (c.1196C>T)?

AlphaMissense predicts likely benign (score 0.3374) — an in-silico prediction, not a clinical call.

RET p.Pro399Leu

c.1196C>T · rs1554818362 · VCV274004

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.3374 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RET-related disorder

Computational evidence

Protein change
AlphaMissense	0.3374	likely benign
REVEL	0.866	moderately pathogenic-leaning
SaProt	LLR -10.60	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.75, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	26.7	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 8.47e-05% European (non-Finnish) · 1/1,180,044 alleles

Overall 6.2e-05% 1/1,613,880 alleles · very rare exomes 1/1,461,534 · genomes 0/152,346 · joint denominator

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.Pro399Leu
Coding: c.1196C>T
MANE Select: NM_020975
dbSNP: rs1554818362
Type: single nucleotide variant
Location: chr10:43109163 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 399: a UniProt-annotated variant site (in hscr1; sporadic form)

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

Disease context

RET-related disorder

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

Similar variants

RET p.Pro399= Likely benign ★★ same residue
RET p.Pro399Arg Uncertain significance ★ ⚠ same residue
RET p.Pro399Ser 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

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-pro399leu (accessed [today's date]).

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