Is RET p.Asp1081= (c.3243T>C) pathogenic?

RET p.Asp1081= (c.3243T>C) is classified Conflicting classifications of pathogenicity in RET (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-24). Ultra-rare (popmax 0.0284%, nfe); Associated with multiple endocrine neoplasia.

What condition is associated with RET p.Asp1081= (c.3243T>C)?

RET p.Asp1081= (c.3243T>C) is associated with multiple endocrine neoplasia, Hirschsprung disease, susceptibility to, 1, multiple endocrine neoplasia type 2B (ClinVar).

How common is RET p.Asp1081= (c.3243T>C) in the general population?

RET p.Asp1081= (c.3243T>C) is ultra-rare (popmax 0.0284%, nfe) (gnomAD).

RET p.Asp1081=

c.3243T>C · rs144192900 · VCV136118

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0284%, nfe)

Conditions

multiple endocrine neoplasia

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 6.2	GERP 2, phastCons 1
Overall
CADD	8.936	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0284% European (non-Finnish) · 335/1,180,028 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0249%

Overall 0.0213% 344/1,614,086 alleles · ultra-rare exomes 327/1,461,868 · genomes 17/152,218 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0284%	3,522
Remaining individualsnot grpmax-eligible	0.0128%	7,811
African / African-American	0.00133%	74,932

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.Asp1081=
Coding: c.3243T>C
MANE Select: NM_020975
dbSNP: rs144192900
Type: single nucleotide variant
Location: chr10:43128167 (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

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

Also linked: Hirschsprung disease, susceptibility to, 1 multiple endocrine neoplasia type 2B pheochromocytoma multiple endocrine neoplasia type 2A hereditary neoplastic syndrome multiple endocrine neoplasia type 2 renal hypodysplasia/aplasia 1

Similar variants

RET p.Asp1081Asn Uncertain significance ★★ ⚠ same residue
RET p.Asp1081Glu Uncertain significance ★ ⚠ same residue
RET p.Asp1081Gly 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-asp1081 (accessed [today's date]).

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