Is SETX p.Arg2136Cys (c.6406C>T) pathogenic?

SETX p.Arg2136Cys (c.6406C>T) is classified Likely pathogenic in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2018-04-01). AlphaMissense: likely benign (0.2774); Absent from gnomAD v4.1.

How common is SETX p.Arg2136Cys (c.6406C>T) in the general population?

SETX p.Arg2136Cys (c.6406C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETX p.Arg2136Cys (c.6406C>T)?

AlphaMissense predicts likely benign (score 0.2774) — an in-silico prediction, not a clinical call.

SETX p.Arg2136Cys

c.6406C>T · rs1554807765 · VCV624372

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2774 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2774	likely benign ⚠ discordant with ClinVar
REVEL	0.861	moderately pathogenic-leaning
SaProt	LLR -5.51	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 32 kb · p 3e-13 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SETX
Protein: p.Arg2136Cys
Coding: c.6406C>T
MANE Select: NM_015046
dbSNP: rs1554807765
Type: single nucleotide variant
Location: chr9:132283404 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 2136: the upf1-type sf1b helicase atp-binding domain; a UniProt-annotated variant site (in als4; no effect on enzyme activity; reduced thermal stability)

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

Similar variants

SETX p.Arg2136His Likely pathogenic ★ ⚠ 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-arg2136cys (accessed [today's date]).

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