Is RET p.Arg418Pro (c.1253G>C) pathogenic?

RET p.Arg418Pro (c.1253G>C) is classified Uncertain significance in RET (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-05). AlphaMissense: likely benign (0.1859); Very rare (popmax 0.000932%, nfe); Associated with Hirschsprung disease, susceptibility to, 1.

What condition is associated with RET p.Arg418Pro (c.1253G>C)?

RET p.Arg418Pro (c.1253G>C) is associated with Hirschsprung disease, susceptibility to, 1, familial medullary thyroid carcinoma, multiple endocrine neoplasia type 2B (ClinVar).

How common is RET p.Arg418Pro (c.1253G>C) in the general population?

RET p.Arg418Pro (c.1253G>C) is very rare (popmax 0.000932%, nfe) (gnomAD).

What do computational predictors say about RET p.Arg418Pro (c.1253G>C)?

AlphaMissense predicts likely benign (score 0.1859) — an in-silico prediction, not a clinical call.

RET p.Arg418Pro

c.1253G>C · rs371731991 · VCV219396

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1859 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Hirschsprung disease, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.1859	likely benign
REVEL	0.579	indeterminate
SaProt	LLR -8.89	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.92	GERP -3.4, phastCons 0.25
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	18.71	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

Grpmax group 0.000932% European (non-Finnish) · 11/1,179,996 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000682% 11/1,612,966 alleles · very rare exomes 11/1,460,628 · genomes 0/152,338 · 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.Arg418Pro
Coding: c.1253G>C
MANE Select: NM_020975
dbSNP: rs371731991
Type: single nucleotide variant
Location: chr10:43109220 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 418: the 'cadherin-like region 4 (cld4)' region

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: familial medullary thyroid carcinoma multiple endocrine neoplasia type 2B pheochromocytoma multiple endocrine neoplasia type 2A hereditary neoplastic syndrome multiple endocrine neoplasia type 2

Similar variants

RET p.Arg418Leu Uncertain significance ★★ ⚠ same residue
RET p.Arg418Ter Pathogenic ★ same residue
RET p.Arg418Gln Conflicting classifications of pathogenicity ★ ⚠ 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-arg418pro (accessed [today's date]).

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