Is GET3 p.Ser346Thr (c.1037G>C) pathogenic?

GET3 p.Ser346Thr (c.1037G>C) is classified Uncertain significance in GET3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-19). AlphaMissense: likely benign (0.0592); Very rare (popmax 8.56e-05%, nfe).

How common is GET3 p.Ser346Thr (c.1037G>C) in the general population?

GET3 p.Ser346Thr (c.1037G>C) is very rare (popmax 8.56e-05%, nfe) (gnomAD).

What do computational predictors say about GET3 p.Ser346Thr (c.1037G>C)?

AlphaMissense predicts likely benign (score 0.0592) — an in-silico prediction, not a clinical call.

GET3 p.Ser346Thr

c.1037G>C · VCV4029351

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0592 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.56e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0592	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -6.48	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 9.8	GERP 1.2, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 76 bp · p 0.29 · regional, not allelic
Overall
CADD	21.3	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 8.56e-05% European (non-Finnish) · 1/1,167,650 alleles

Overall 6.93e-05% 1/1,443,222 alleles · very rare

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: GET3
Protein: p.Ser346Thr
Coding: c.1037G>C
MANE Select: NM_004317
Type: single nucleotide variant
Location: chr19:12748094 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 79.69 · 4 PDB
Residue 346: a UniProt-annotated variant site (in cmd2h; when associated in cis with variant w-289)

Full GET3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GET3 p.Ala112Gly Uncertain significance ★ ⚠ same type
GET3 p.Ala112Val Uncertain significance ★ ⚠ same type
GET3 p.Ala82Thr Uncertain significance ★ ⚠ same type
GET3 p.Arg230His Uncertain significance ★ ⚠ same type
GET3 p.Arg35Cys Uncertain significance ★ ⚠ same type
GET3 p.Arg65Cys Uncertain significance ★ ⚠ same type
GET3 p.Arg65His Uncertain significance ★ ⚠ same type
GET3 p.Asp284Asn Uncertain significance ★ ⚠ same type

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/get3-p-ser346thr (accessed [today's date]).

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