Is RET p.Gly830Arg (c.2488G>A) pathogenic?

RET p.Gly830Arg (c.2488G>A) is classified Conflicting classifications of pathogenicity in RET (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-28). AlphaMissense: likely benign (0.0886); Ultra-rare (popmax 0.0446%, eas); Associated with multiple endocrine neoplasia type 2B.

What condition is associated with RET p.Gly830Arg (c.2488G>A)?

RET p.Gly830Arg (c.2488G>A) is associated with multiple endocrine neoplasia type 2B, Hirschsprung disease, susceptibility to, 1, familial medullary thyroid carcinoma (ClinVar).

How common is RET p.Gly830Arg (c.2488G>A) in the general population?

RET p.Gly830Arg (c.2488G>A) is ultra-rare (popmax 0.0446%, eas) (gnomAD).

What do computational predictors say about RET p.Gly830Arg (c.2488G>A)?

AlphaMissense predicts likely benign (score 0.0886) — an in-silico prediction, not a clinical call.

RET p.Gly830Arg

c.2488G>A · rs200127630 · VCV372078

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0886 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple endocrine neoplasia type 2B

Computational evidence

Protein change
AlphaMissense	0.0886	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -7.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -3.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	17.71	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 0.0446% East Asian · 20/44,884 alleles

Filtering AF 0.0295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0246%

Overall 0.00136% 22/1,612,834 alleles · ultra-rare exomes 18/1,460,498 · genomes 4/152,336 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0446%	2,244
Remaining individualsnot grpmax-eligible	0.0032%	31,221

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.Gly830Arg
Coding: c.2488G>A
MANE Select: NM_020975
dbSNP: rs200127630
Type: single nucleotide variant
Location: chr10:43119626 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 830: a UniProt-annotated variant site (in hscr1); the protein kinase domain

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 hereditary neoplastic syndrome multiple endocrine neoplasia type 2

Similar variants

RET p.Gly830Glu Uncertain significance ★★ ⚠ same residue
RET p.Gly830= Likely benign ★ 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
RET p.Arg897Gln 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-gly830arg (accessed [today's date]).

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