Is GET3 p.Arg65Cys (c.193C>T) pathogenic?

GET3 p.Arg65Cys (c.193C>T) is classified Uncertain significance in GET3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-24). AlphaMissense: likely pathogenic (0.8418); Very rare (popmax 0.00133%, afr).

How common is GET3 p.Arg65Cys (c.193C>T) in the general population?

GET3 p.Arg65Cys (c.193C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about GET3 p.Arg65Cys (c.193C>T)?

AlphaMissense predicts likely pathogenic (score 0.8418) — an in-silico prediction, not a clinical call.

GET3 p.Arg65Cys

c.193C>T · rs930973539 · VCV2551594

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8418 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8418	likely pathogenic
REVEL	0.488	indeterminate
SaProt	LLR -15.12	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP 0.25, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 10 kb · p 6.9e-16 · regional, not allelic
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00133% African / African-American · 1/74,910 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,613,978 alleles · very rare exomes 4/1,461,858 · genomes 3/152,120 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
African / African-Americangrpmax	0.00133%	74,910
European (non-Finnish)	0.000424%	236,004

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: GET3
Protein: p.Arg65Cys
Coding: c.193C>T
MANE Select: NM_004317
dbSNP: rs930973539
Type: single nucleotide variant
Location: chr19:12738542 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 79.69 · 4 PDB

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

Similar variants

GET3 p.Arg65His Uncertain significance ★ ⚠ same residue
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.Asp284Asn Uncertain significance ★ ⚠ same type
GET3 p.Asp304His 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-arg65cys (accessed [today's date]).

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