Is RET p.Arg175Pro (c.524G>C) pathogenic?

RET p.Arg175Pro (c.524G>C) is classified Uncertain significance in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-27). AlphaMissense: likely pathogenic (0.6659); Absent from gnomAD v4.1.

How common is RET p.Arg175Pro (c.524G>C) in the general population?

RET p.Arg175Pro (c.524G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RET p.Arg175Pro (c.524G>C)?

AlphaMissense predicts likely pathogenic (score 0.6659) — an in-silico prediction, not a clinical call.

RET p.Arg175Pro

c.524G>C · VCV3337517

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6659 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6659	likely pathogenic
REVEL	0.248	benign-leaning
SaProt	LLR -8.92	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.5	GERP 0.62, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	28.7	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

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.Arg175Pro
Coding: c.524G>C
MANE Select: NM_020975
Type: single nucleotide variant
Location: chr10:43102528 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 175: a β-strand; the cadherin domain; a UniProt-annotated variant site (in hscr1)

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

Similar variants

RET p.Arg175Cys Uncertain significance ★★ ⚠ same residue
RET p.Arg175His Uncertain significance ★★ ⚠ same residue
RET p.Arg175Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
RET p.Arg175Leu Uncertain significance ★ ⚠ same residue
RET p.Arg175Ser Uncertain significance ★ ⚠ 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

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-arg175pro (accessed [today's date]).

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