Is SETX p.His1989Arg (c.5966A>G) pathogenic?

SETX p.His1989Arg (c.5966A>G) is classified Uncertain significance in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-08). AlphaMissense: likely benign (0.0673); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SETX p.His1989Arg (c.5966A>G)?

SETX p.His1989Arg (c.5966A>G) is associated with Inborn genetic diseases (ClinVar).

How common is SETX p.His1989Arg (c.5966A>G) in the general population?

SETX p.His1989Arg (c.5966A>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about SETX p.His1989Arg (c.5966A>G)?

AlphaMissense predicts likely benign (score 0.0673) — an in-silico prediction, not a clinical call.

SETX p.His1989Arg

c.5966A>G · VCV3440280

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0673 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0673	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -5.57	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 -0.97	GERP 0.58
Regional constraint	o/e 0.70	unconstrained · MANE · 32 kb · p 3e-13 · regional, not allelic
Overall
CADD	4.061	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 0.000424% European (non-Finnish) · 5/1,180,054 alleles

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

Overall 0.00031% 5/1,614,118 alleles · very rare exomes 4/1,461,880 · genomes 1/152,238 · joint denominator

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: SETX
Protein: p.His1989Arg
Coding: c.5966A>G
MANE Select: NM_015046
Type: single nucleotide variant
Location: chr9:132296012 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 1989: the upf1-type sf1b helicase atp-binding domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETX p.Arg1363Ter Pathogenic ★★ same condition
SETX p.Ala1945Val Uncertain significance ★★ ⚠ same condition
SETX p.Ala2596Pro Uncertain significance ★★ ⚠ same condition
SETX p.Ala488Thr Uncertain significance ★★ ⚠ same condition
SETX p.Arg1214Ser Uncertain significance ★★ ⚠ same condition
SETX p.Arg1302Leu Uncertain significance ★★ same condition
SETX p.Arg1846His Uncertain significance ★★ ⚠ same condition
SETX p.Arg1846Leu Uncertain significance ★★ ⚠ 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/setx-p-his1989arg (accessed [today's date]).

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