Is RET p.Ala373= (c.1119G>A) pathogenic?

RET p.Ala373= (c.1119G>A) is classified Conflicting classifications of pathogenicity in RET (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-03-01). Rare (popmax 0.227%, afr); Associated with multiple endocrine neoplasia type 2.

What condition is associated with RET p.Ala373= (c.1119G>A)?

RET p.Ala373= (c.1119G>A) is associated with multiple endocrine neoplasia type 2, Hirschsprung disease, susceptibility to, 1, multiple endocrine neoplasia type 2B (ClinVar).

How common is RET p.Ala373= (c.1119G>A) in the general population?

RET p.Ala373= (c.1119G>A) is rare (popmax 0.227%, afr) (gnomAD).

How is Multiple endocrine neoplasia type 2 inherited?

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

RET p.Ala373=

c.1119G>A · rs113931414 · VCV287736

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

rare (popmax 0.227%, afr)

Conditions

multiple endocrine neoplasia type 2

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 -8.5	GERP -3.7
Overall
CADD	2.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.227% African / African-American · 170/75,010 alleles

Filtering AF 0.199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.188%

Overall 0.0143% 230/1,613,752 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.227%	441
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0464%	2,155
Admixed American	0.0317%	3,159
East Asian	0.00446%	22,435
European (non-Finnish)	0.000593%	168,575

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.Ala373=
Coding: c.1119G>A
MANE Select: NM_020975
dbSNP: rs113931414
Type: single nucleotide variant
Location: chr10:43109086 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 373: the 'cadherin-like region 3 (cld3)' region

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

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.Ala373Glu Uncertain significance ★★ ⚠ same residue
RET p.Ala373Val Benign/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-ala373 (accessed [today's date]).

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