Is RET p.Ser445Pro (c.1333T>C) pathogenic?

RET p.Ser445Pro (c.1333T>C) is classified Uncertain significance in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely benign (0.0845); Absent from gnomAD v4.1.

How common is RET p.Ser445Pro (c.1333T>C) in the general population?

RET p.Ser445Pro (c.1333T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RET p.Ser445Pro (c.1333T>C)?

AlphaMissense predicts likely benign (score 0.0845) — an in-silico prediction, not a clinical call.

RET p.Ser445Pro

c.1333T>C · VCV4882568

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0845 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0845	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -7.34	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 -0.09	GERP -2.3
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	0.819	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RET
Protein: p.Ser445Pro
Coding: c.1333T>C
MANE Select: NM_020975
Type: single nucleotide variant
Location: chr10:43111276 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 445: the 'cadherin-like region 4 (cld4)' region

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

Similar variants

RET p.Ser445Cys Uncertain significance ★★ ⚠ same residue
RET p.Ser445= Conflicting classifications of pathogenicity ★ same residue
RET c.1759+1G>A Pathogenic/Likely pathogenic ★★ same type
RET c.1879+1G>A Pathogenic/Likely pathogenic ★★ same type
RET p.Arg180Ter Pathogenic ★★ same type
RET p.Arg77Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
RET p.Arg873Trp Likely pathogenic ★★ same type
RET p.Arg897Gln Pathogenic ★★ ⚠ same type

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-ser445pro (accessed [today's date]).

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