Is RET p.Lys1007Met (c.3020A>T) pathogenic?

RET p.Lys1007Met (c.3020A>T) is classified Uncertain significance in RET (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-14). AlphaMissense: likely benign (0.3272); Very rare (popmax 0.00144%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Lys1007Met (c.3020A>T)?

RET p.Lys1007Met (c.3020A>T) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Lys1007Met (c.3020A>T) in the general population?

RET p.Lys1007Met (c.3020A>T) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about RET p.Lys1007Met (c.3020A>T)?

AlphaMissense predicts likely benign (score 0.3272) — an in-silico prediction, not a clinical call.

RET p.Lys1007Met

c.3020A>T · rs759798237 · VCV2625014

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3272 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3272	likely benign
REVEL	0.703	pathogenic-leaning
SaProt	LLR -8.75	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 4,468 bp · p 0.69 · regional, not allelic
Overall
CADD	31.0	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

Grpmax group 0.00144% European (non-Finnish) · 17/1,180,030 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00116% 17/1,461,866 alleles · very rare

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.Lys1007Met
Coding: c.3020A>T
MANE Select: NM_020975
dbSNP: rs759798237
Type: single nucleotide variant
Location: chr10:43124963 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 1007: an α-helix; the protein kinase domain

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

Also linked: multiple endocrine neoplasia type 2

Similar variants

RET p.Lys1007Asn Uncertain significance ★★ same residue
RET p.Lys1007Glu Uncertain significance ★★ ⚠ same residue
RET p.Lys1007Thr Uncertain significance ★★ ⚠ 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-lys1007met (accessed [today's date]).

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