Is RET p.Ala2= (c.6G>A) pathogenic?

RET p.Ala2= (c.6G>A) is classified Likely benign in RET (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-10). Ultra-rare (popmax 0.0125%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Ala2= (c.6G>A)?

RET p.Ala2= (c.6G>A) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Ala2= (c.6G>A) in the general population?

RET p.Ala2= (c.6G>A) is ultra-rare (popmax 0.0125%, amr) (gnomAD).

RET p.Ala2=

c.6G>A · rs1243883489 · VCV767548

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, amr)

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 0.77	GERP -2.4, phastCons 1
Overall
CADD	14.26	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0125% Admixed American · 6/48,026 alleles

Filtering AF 0.00537% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00364%

Overall 0.000798% 12/1,504,372 alleles · ultra-rare exomes 6/1,352,396 · genomes 6/151,976 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0125%	8,004
African / African-American	0.00144%	69,552
South Asian	0.00124%	80,844
European (non-Finnish)	0.000353%	283,034

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.Ala2=
Coding: c.6G>A
MANE Select: NM_020975
dbSNP: rs1243883489
Type: single nucleotide variant
Location: chr10:43077264 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB

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: multiple endocrine neoplasia type 2

Similar variants

RET p.Ala2Glu Uncertain significance ★★ ⚠ same residue
RET p.Ala2Val Uncertain significance ★ ⚠ same residue
RET p.Ala2_Lys3insMetAla 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-ala2 (accessed [today's date]).

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