Is GET3 p.Arg65His (c.194G>A) pathogenic?

GET3 p.Arg65His (c.194G>A) is classified Uncertain significance in GET3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-26). AlphaMissense: likely pathogenic (0.8053); Very rare (popmax 0.00223%, eas).

How common is GET3 p.Arg65His (c.194G>A) in the general population?

GET3 p.Arg65His (c.194G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about GET3 p.Arg65His (c.194G>A)?

AlphaMissense predicts likely pathogenic (score 0.8053) — an in-silico prediction, not a clinical call.

GET3 p.Arg65His

c.194G>A · VCV3281226

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8053 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8053	likely pathogenic
REVEL	0.417	indeterminate
SaProt	LLR -14.81	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.42 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 10 kb · p 6.9e-16 · regional, not allelic
Overall
CADD	32.0	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 0.00223% East Asian · 1/44,882 alleles

Overall 0.000124% 2/1,614,162 alleles · very rare exomes 2/1,461,874 · genomes 0/152,288 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
European (non-Finnish)	8.47e-05%	1,180,038

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.Arg65His
Coding: c.194G>A
MANE Select: NM_004317
Type: single nucleotide variant
Location: chr19:12738543 (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.Arg65Cys 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-arg65his (accessed [today's date]).

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