Is SETX p.Phe565Leu (c.1693T>C) pathogenic?

SETX p.Phe565Leu (c.1693T>C) is classified Benign/Likely benign in SETX (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-05-08). AlphaMissense: likely pathogenic (0.8021); Rare (popmax 0.416%, amr); Associated with amyotrophic lateral sclerosis type 4.

What condition is associated with SETX p.Phe565Leu (c.1693T>C)?

SETX p.Phe565Leu (c.1693T>C) is associated with amyotrophic lateral sclerosis type 4, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (ClinVar).

How common is SETX p.Phe565Leu (c.1693T>C) in the general population?

SETX p.Phe565Leu (c.1693T>C) is rare (popmax 0.416%, amr) (gnomAD).

How is Amyotrophic lateral sclerosis type 4 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SETX p.Phe565Leu (c.1693T>C)?

AlphaMissense predicts likely pathogenic (score 0.8021) — an in-silico prediction, not a clinical call.

SETX p.Phe565Leu

c.1693T>C · rs143982186 · VCV365370

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.8021 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.416%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 4

Computational evidence

Protein change
AlphaMissense	0.8021	likely pathogenic
REVEL	0.25	benign-leaning
SaProt	LLR -7.73	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 522 bp · p 0.2 · regional, not allelic
Overall
CADD	17.62	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 0.416% Admixed American · 250/60,030 alleles

Filtering AF 0.374% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.358%

Overall 0.0169% 273/1,614,196 alleles · rare exomes 213/1,461,820 · genomes 60/152,376 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.416%	240
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.016%	6,251
African / African-American	0.00666%	15,016
South Asian	0.0022%	45,545
European (non-Finnish)	0.000424%	236,003

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.Phe565Leu
Coding: c.1693T>C
MANE Select: NM_015046
dbSNP: rs143982186
Type: single nucleotide variant
Location: chr9:132329905 (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

Disease context

amyotrophic lateral sclerosis type 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

For Amyotrophic lateral sclerosis type 4 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Childhood

Similar variants

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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-phe565leu (accessed [today's date]).

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