Is RET p.Arg982Ser (c.2944C>A) pathogenic?

RET p.Arg982Ser (c.2944C>A) is classified Conflicting classifications of pathogenicity in RET (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-07-03). AlphaMissense: likely benign (0.1397); Very rare (popmax 0.00133%, afr); Associated with multiple endocrine neoplasia type 2.

What condition is associated with RET p.Arg982Ser (c.2944C>A)?

RET p.Arg982Ser (c.2944C>A) is associated with multiple endocrine neoplasia type 2, hereditary neoplastic syndrome (ClinVar).

How common is RET p.Arg982Ser (c.2944C>A) in the general population?

RET p.Arg982Ser (c.2944C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Multiple endocrine neoplasia type 2 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RET p.Arg982Ser (c.2944C>A)?

AlphaMissense predicts likely benign (score 0.1397) — an in-silico prediction, not a clinical call.

RET p.Arg982Ser

c.2944C>A · rs17158558 · VCV3069281

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1397 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple endocrine neoplasia type 2

Computational evidence

Protein change
AlphaMissense	0.1397	likely benign
REVEL	0.148	moderately benign-leaning
SaProt	LLR -5.37	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 1.8	GERP -4, phastCons 0.1
Regional constraint	o/e 0.97	unconstrained · MANE · 4,468 bp · p 0.69 · regional, not allelic
Overall
CADD	12.74	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 0.00133% African / African-American · 1/75,040 alleles

Overall 6.84e-05% 1/1,461,622 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.Arg982Ser
Coding: c.2944C>A
MANE Select: NM_020975
dbSNP: rs17158558
Type: single nucleotide variant
Location: chr10:43124887 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 982: a UniProt-annotated variant site (in); an α-helix; the protein kinase domain

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

Disease context

multiple endocrine neoplasia type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Multiple endocrine neoplasia type 2 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

RET p.Arg982Leu Uncertain significance ★★ ⚠ same residue
RET p.Arg982Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
RET p.Arg982His Conflicting classifications of pathogenicity ★ ⚠ 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-arg982ser (accessed [today's date]).

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