Is RET p.Pro305Ser (c.913C>T) pathogenic?

RET p.Pro305Ser (c.913C>T) is classified Uncertain significance in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-15). AlphaMissense: ambiguous (0.3535); Absent from gnomAD v4.1; Associated with multiple endocrine neoplasia type 2B.

What condition is associated with RET p.Pro305Ser (c.913C>T)?

RET p.Pro305Ser (c.913C>T) is associated with multiple endocrine neoplasia type 2B, Hirschsprung disease, susceptibility to, 1, familial medullary thyroid carcinoma (ClinVar).

How common is RET p.Pro305Ser (c.913C>T) in the general population?

RET p.Pro305Ser (c.913C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RET p.Pro305Ser (c.913C>T)?

AlphaMissense predicts ambiguous (score 0.3535) — an in-silico prediction, not a clinical call.

RET p.Pro305Ser

c.913C>T · VCV3594598

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3535 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

multiple endocrine neoplasia type 2B

Computational evidence

Protein change
AlphaMissense	0.3535	ambiguous
REVEL	0.386	indeterminate
SaProt	LLR -6.44	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	22.4	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.Pro305Ser
Coding: c.913C>T
MANE Select: NM_020975
Type: single nucleotide variant
Location: chr10:43106421 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 305: the 'cadherin-like region 3 (cld3)' region

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

Disease context

multiple endocrine neoplasia type 2B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Hirschsprung disease, susceptibility to, 1 familial medullary thyroid carcinoma pheochromocytoma multiple endocrine neoplasia type 2A

Similar variants

RET p.Pro305= Likely benign ★ same residue
RET c.1879+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET p.Arg180Ter Pathogenic ★★ same condition
RET p.Arg873Trp Likely pathogenic ★★ same condition
RET p.Arg897Gln Pathogenic ★★ ⚠ same condition
RET p.Asp631Tyr Pathogenic ★★ ⚠ same condition
RET p.Cys609Arg Pathogenic ★★ same condition
RET p.Cys609Gly 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-pro305ser (accessed [today's date]).

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