Is SETX p.Arg128His (c.383G>A) pathogenic?

SETX p.Arg128His (c.383G>A) is classified Uncertain significance in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2016-09-08). AlphaMissense: likely benign (0.0844); Very rare (popmax 0.0033%, sas).

How common is SETX p.Arg128His (c.383G>A) in the general population?

SETX p.Arg128His (c.383G>A) is very rare (popmax 0.0033%, sas) (gnomAD).

What do computational predictors say about SETX p.Arg128His (c.383G>A)?

AlphaMissense predicts likely benign (score 0.0844) — an in-silico prediction, not a clinical call.

SETX p.Arg128His

c.383G>A · rs749887957 · VCV448325

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0844 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0844	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	LLR -9.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.30	donor gain · deltas
Pangolin	Δ0.29	gain · loss 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2	GERP 0.68, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 3,163 bp · p 0.74 · regional, not allelic
Overall
CADD	21.7	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 0.0033% South Asian · 3/91,008 alleles

Filtering AF 0.000876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000869% 14/1,611,322 alleles · very rare exomes 14/1,459,110 · genomes 0/152,212 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,336
European (non-Finnish)	0.000934%	107,058

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.Arg128His
Coding: c.383G>A
MANE Select: NM_015046
dbSNP: rs749887957
Type: single nucleotide variant
Location: chr9:132346266 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93

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

Similar variants

SETX p.Arg128Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
SETX p.Arg111Ter Pathogenic ★★ same type
SETX p.Arg1363Ter Pathogenic ★★ same type
SETX p.Arg1606Ter Pathogenic ★★ same type
SETX p.Arg1778Ter Pathogenic/Likely pathogenic ★★ same type
SETX p.Arg2098Ter Pathogenic ★★ same type
SETX p.Arg332Trp Pathogenic/Likely pathogenic ★★ same type
SETX p.Arg778Ter Pathogenic/Likely pathogenic ★★ 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/setx-p-arg128his (accessed [today's date]).

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