Is RET p.Pro996= (c.2988G>A) pathogenic?

RET p.Pro996= (c.2988G>A) is classified Conflicting classifications of pathogenicity in RET (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0406%, sas); Associated with familial medullary thyroid carcinoma.

What condition is associated with RET p.Pro996= (c.2988G>A)?

RET p.Pro996= (c.2988G>A) is associated with familial medullary thyroid carcinoma, appendicitis, Hirschsprung disease, susceptibility to, 1 (ClinVar).

How common is RET p.Pro996= (c.2988G>A) in the general population?

RET p.Pro996= (c.2988G>A) is ultra-rare (popmax 0.0406%, sas) (gnomAD).

How is Isolated familial medullary thyroid carcinoma inherited?

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

RET p.Pro996=

c.2988G>A · rs145798106 · VCV215914

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0406%, sas)

Conditions

familial medullary thyroid carcinoma

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 -3	GERP -4
Overall
CADD	0.563	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0406% South Asian · 37/91,082 alleles

Filtering AF 0.0303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0267%

Overall 0.0107% 172/1,614,092 alleles · ultra-rare exomes 151/1,461,870 · genomes 21/152,222 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0406%	2,462
Finnishnot grpmax-eligible	0.0125%	8,006
African / African-American	0.012%	8,326
European (non-Finnish)	0.00924%	10,826
Remaining individualsnot grpmax-eligible	0.008%	12,497
Admixed American	0.005%	20,004
East Asian	0.00223%	44,892

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.Pro996=
Coding: c.2988G>A
MANE Select: NM_020975
dbSNP: rs145798106
Type: single nucleotide variant
Location: chr10:43124931 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 996: the protein kinase domain

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

Disease context

familial medullary thyroid carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Isolated familial medullary thyroid carcinoma (Orphanet):

Inheritance: Autosomal dominant

Similar variants

RET p.Pro996Leu 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
RET p.Arg897Gln Pathogenic ★★ ⚠ same condition
RET p.Arg897Ter 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-pro996 (accessed [today's date]).

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