Is RET p.Pro992Ala (c.2974C>G) pathogenic?

RET p.Pro992Ala (c.2974C>G) is classified Uncertain significance in RET (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-21). AlphaMissense: likely benign (0.0797); Very rare (popmax 8.47e-05%, nfe); Associated with multiple endocrine neoplasia type 2.

What condition is associated with RET p.Pro992Ala (c.2974C>G)?

RET p.Pro992Ala (c.2974C>G) is associated with multiple endocrine neoplasia type 2, hereditary neoplastic syndrome (ClinVar).

How common is RET p.Pro992Ala (c.2974C>G) in the general population?

RET p.Pro992Ala (c.2974C>G) is very rare (popmax 8.47e-05%, nfe) (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.Pro992Ala (c.2974C>G)?

AlphaMissense predicts likely benign (score 0.0797) — an in-silico prediction, not a clinical call.

RET p.Pro992Ala

c.2974C>G · rs2133016623 · VCV2587884

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0797 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

multiple endocrine neoplasia type 2

Computational evidence

Protein change
AlphaMissense	0.0797	likely benign
REVEL	0.346	indeterminate
SaProt	LLR -8.86	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.92, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 4,468 bp · p 0.69 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,048 alleles

Overall 6.2e-05% 1/1,614,200 alleles · very rare exomes 1/1,461,860 · genomes 0/152,340 · joint denominator

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.Pro992Ala
Coding: c.2974C>G
MANE Select: NM_020975
dbSNP: rs2133016623
Type: single nucleotide variant
Location: chr10:43124917 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 992: 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.Pro992Gln Uncertain significance ★★ ⚠ same residue
RET p.Pro992= Likely benign ★★ same residue
RET p.Pro992Arg Uncertain significance ★ ⚠ same residue
RET p.Pro992Leu 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

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-pro992ala (accessed [today's date]).

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