Is SETX p.Cys1368Phe (c.4103G>T) pathogenic?

SETX p.Cys1368Phe (c.4103G>T) is classified Conflicting classifications of pathogenicity in SETX (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-06-02). AlphaMissense: likely benign (0.0826); Very rare (popmax 0.00223%, eas); Associated with SETX-related disorder.

How common is SETX p.Cys1368Phe (c.4103G>T) in the general population?

SETX p.Cys1368Phe (c.4103G>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about SETX p.Cys1368Phe (c.4103G>T)?

AlphaMissense predicts likely benign (score 0.0826) — an in-silico prediction, not a clinical call.

SETX p.Cys1368Phe

Q: What condition is associated with SETX p.Cys1368Phe (c.4103G>T)?

SETX p.Cys1368Phe (c.4103G>T) is associated with SETX-related disorder, amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

c.4103G>T · rs1445388214 · VCV568959

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0826 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

SETX-related disorder

Computational evidence

Protein change
AlphaMissense	0.0826	likely benign
REVEL	0.295	indeterminate
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5.8	GERP -3.6
Regional constraint	o/e 1.13	unconstrained · MANE · 3,399 bp · p 2.4e-06 · regional, not allelic
Overall
CADD	0.004	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

Grpmax group 0.00223% East Asian · 1/44,892 alleles

Overall 0.00031% 5/1,614,106 alleles · very rare exomes 5/1,461,770 · genomes 0/152,336 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,627
East Asiangrpmax	0.00223%	44,892

Remaining individuals 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: SETX
Protein: p.Cys1368Phe
Coding: c.4103G>T
MANE Select: NM_015046
dbSNP: rs1445388214
Type: single nucleotide variant
Location: chr9:132327495 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.93
Residue 1368: the 'disordered' region

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

Disease context

Also linked: amyotrophic lateral sclerosis type 4 spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Similar variants

SETX p.Arg111Ter Pathogenic ★★ same condition
SETX p.Arg1363Ter Pathogenic ★★ same condition
SETX p.Arg1606Ter Pathogenic ★★ same condition
SETX p.Arg1778Ter Pathogenic/Likely pathogenic ★★ same condition
SETX p.Arg2098Ter Pathogenic ★★ same condition
SETX p.Arg332Trp Pathogenic/Likely pathogenic ★★ same condition
SETX p.Arg778Ter Pathogenic/Likely pathogenic ★★ same condition
SETX p.Gln1695Ter Pathogenic/Likely pathogenic ★★ 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-cys1368phe (accessed [today's date]).

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