Is RET p.Ala46= (c.138C>T) pathogenic?

RET p.Ala46= (c.138C>T) is classified Likely benign in RET (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-13). Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Ala46= (c.138C>T)?

RET p.Ala46= (c.138C>T) is associated with hereditary neoplastic syndrome, Hirschsprung disease, susceptibility to, 1, familial medullary thyroid carcinoma (ClinVar).

How common is RET p.Ala46= (c.138C>T) in the general population?

RET p.Ala46= (c.138C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

RET p.Ala46=

c.138C>T · rs1177522214 · VCV737891

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hereditary neoplastic syndrome

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 -14	GERP -3.4
Overall
CADD	0.055	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,880 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000753% 11/1,461,588 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,835
East Asiangrpmax	0.00223%	44,880
Admixed American	0.00167%	60,030
European (non-Finnish)	0.000508%	196,672

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala46=
Coding: c.138C>T
MANE Select: NM_020975
dbSNP: rs1177522214
Type: single nucleotide variant
Location: chr10:43100523 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 46: the 'cadherin-like region 1 (cld1)' region

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Hirschsprung disease, susceptibility to, 1 familial medullary thyroid carcinoma multiple endocrine neoplasia type 2B pheochromocytoma multiple endocrine neoplasia type 2A multiple endocrine neoplasia type 2

Similar variants

RET p.Ala46Val Uncertain significance ★ ⚠ same residue
RET p.Ala46Ser 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

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-ala46 (accessed [today's date]).

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