Is RET p.Ala228Ser (c.682G>T) pathogenic?

RET p.Ala228Ser (c.682G>T) is classified Uncertain significance in RET (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-07). AlphaMissense: likely benign (0.0839); Very rare (popmax 0.000125%); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Ala228Ser (c.682G>T)?

RET p.Ala228Ser (c.682G>T) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Ala228Ser (c.682G>T) in the general population?

RET p.Ala228Ser (c.682G>T) is very rare (popmax 0.000125%) (gnomAD).

What do computational predictors say about RET p.Ala228Ser (c.682G>T)?

AlphaMissense predicts likely benign (score 0.0839) — an in-silico prediction, not a clinical call.

RET p.Ala228Ser

c.682G>T · rs760813493 · VCV186971

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0839 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000125%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0839	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -6.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -3.3, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	14.73	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 0.000125%

Overall 0.000125% 2/1,594,854 alleles · very rare exomes 2/1,442,528 · genomes 0/152,326 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00341%	29,352
Finnishnot grpmax-eligible	0.00186%	53,724

Ashkenazi Jewish 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.Ala228Ser
Coding: c.682G>T
MANE Select: NM_020975
dbSNP: rs760813493
Type: single nucleotide variant
Location: chr10:43105008 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 228: the cadherin domain

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.Ala228Asp Uncertain significance ★★ ⚠ same residue
RET p.Ala228Thr Uncertain significance ★★ ⚠ same residue
RET p.Ala228Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
RET p.Ala228Val 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-ala228ser (accessed [today's date]).

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