Is SETX p.Phe645Tyr (c.1934T>A) pathogenic?

SETX p.Phe645Tyr (c.1934T>A) is classified Uncertain significance in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-01). AlphaMissense: likely benign (0.0906); Absent from gnomAD v4.1; Associated with amyotrophic lateral sclerosis.

What condition is associated with SETX p.Phe645Tyr (c.1934T>A)?

SETX p.Phe645Tyr (c.1934T>A) is associated with amyotrophic lateral sclerosis (ClinVar).

How common is SETX p.Phe645Tyr (c.1934T>A) in the general population?

SETX p.Phe645Tyr (c.1934T>A) is absent from gnomAD v4.1 (gnomAD).

How is Amyotrophic lateral sclerosis inherited?

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

What do computational predictors say about SETX p.Phe645Tyr (c.1934T>A)?

AlphaMissense predicts likely benign (score 0.0906) — an in-silico prediction, not a clinical call.

SETX p.Phe645Tyr

c.1934T>A · rs2131457188 · VCV1343325

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0906 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis

Computational evidence

Protein change
AlphaMissense	0.0906	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -6.92	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 2.3	GERP -0.63, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 3,399 bp · p 2.4e-06 · regional, not allelic
Overall
CADD	12.86	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

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.Phe645Tyr
Coding: c.1934T>A
MANE Select: NM_015046
dbSNP: rs2131457188
Type: single nucleotide variant
Location: chr9:132329664 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Amyotrophic lateral sclerosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

SETX p.Arg2083Ile Uncertain significance ★★ ⚠ same condition
SETX p.Ile1016Thr Uncertain significance ★★ ⚠ same condition
SETX p.Val1089Met Uncertain significance ★★ ⚠ same condition
SETX c.7199+8A>G Conflicting classifications of pathogenicity ★ same condition
SETX p.Arg20Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
SETX p.Asp1077Asn Conflicting classifications of pathogenicity ★ ⚠ same condition
SETX p.Ile2547Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
SETX p.Ile466Met 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-phe645tyr (accessed [today's date]).

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