Is RET p.Ala640Pro (c.1918G>C) pathogenic?

RET p.Ala640Pro (c.1918G>C) is classified Uncertain significance in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-13). AlphaMissense: ambiguous (0.4978); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Ala640Pro (c.1918G>C)?

RET p.Ala640Pro (c.1918G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is RET p.Ala640Pro (c.1918G>C) in the general population?

RET p.Ala640Pro (c.1918G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RET p.Ala640Pro (c.1918G>C)?

AlphaMissense predicts ambiguous (score 0.4978) — an in-silico prediction, not a clinical call.

RET p.Ala640Pro

c.1918G>C · VCV4863261

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4978 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4978	ambiguous
REVEL	0.576	indeterminate
SaProt	LLR -13.49	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 1.9, phastCons 0.99
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	20.3	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.Ala640Pro
Coding: c.1918G>C
MANE Select: NM_020975
Type: single nucleotide variant
Location: chr10:43114518 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 640: a UniProt-annotated variant site (in men2a)

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RET p.Ala640= Conflicting classifications of pathogenicity ★ same residue
RET p.Ala640Thr Uncertain significance ★ ⚠ same residue
RET p.Ala640Gly Pathogenic ⚠ same residue
RET c.1759+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET p.Arg873Trp Likely 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-ala640pro (accessed [today's date]).

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