Is RET p.Arg540= (c.1620G>A) pathogenic?

RET p.Arg540= (c.1620G>A) is classified Conflicting classifications of pathogenicity in RET (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-22). Very rare (popmax 0.00236%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Arg540= (c.1620G>A)?

RET p.Arg540= (c.1620G>A) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Arg540= (c.1620G>A) in the general population?

RET p.Arg540= (c.1620G>A) is very rare (popmax 0.00236%, sas) (gnomAD).

RET p.Arg540=

c.1620G>A · rs776381183 · VCV1612428

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00236%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.066	GERP -2.8, phastCons 0.45
Overall
CADD	8.12	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00236% South Asian · 2/84,776 alleles

Filtering AF 0.000392% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000147%

Overall 0.00032% 5/1,560,786 alleles · very rare exomes 4/1,408,542 · genomes 1/152,244 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00236%	42,388
Remaining individualsnot grpmax-eligible	0.00165%	60,460
European (non-Finnish)	0.000174%	575,944

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.Arg540=
Coding: c.1620G>A
MANE Select: NM_020975
dbSNP: rs776381183
Type: single nucleotide variant
Location: chr10:43112196 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB

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.Arg540Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
RET p.Arg540Lys Uncertain significance ★ ⚠ same residue
RET p.Arg540Met 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-arg540 (accessed [today's date]).

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