Is SETX p.Phe1812Ile (c.5434T>A) pathogenic?

SETX p.Phe1812Ile (c.5434T>A) is classified Uncertain significance in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-25). AlphaMissense: likely pathogenic (0.609); Very rare (popmax 0.00144%, nfe); Associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2.

How common is SETX p.Phe1812Ile (c.5434T>A) in the general population?

SETX p.Phe1812Ile (c.5434T>A) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about SETX p.Phe1812Ile (c.5434T>A)?

AlphaMissense predicts likely pathogenic (score 0.609) — an in-silico prediction, not a clinical call.

SETX p.Phe1812Ile

Q: What condition is associated with SETX p.Phe1812Ile (c.5434T>A)?

SETX p.Phe1812Ile (c.5434T>A) is associated with spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, amyotrophic lateral sclerosis type 4 (ClinVar).

Q: How is Spinocerebellar ataxia with axonal neuropathy type 2 inherited?

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

c.5434T>A · rs763771426 · VCV1405681

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.609 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

Computational evidence

Protein change
AlphaMissense	0.609	likely pathogenic
REVEL	0.56	indeterminate
SaProt	LLR -5.99	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.3	GERP 1.5, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 29 kb · p 0.045 · regional, not allelic
Overall
CADD	25.3	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 0.00144% European (non-Finnish) · 17/1,179,888 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00112% 18/1,613,566 alleles · very rare exomes 16/1,461,378 · genomes 2/152,188 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00157%	63,824
European (non-Finnish)grpmax	0.00144%	69,405

Finnish 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.Phe1812Ile
Coding: c.5434T>A
MANE Select: NM_015046
dbSNP: rs763771426
Type: single nucleotide variant
Location: chr9:132300744 (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

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: amyotrophic lateral sclerosis type 4

For Spinocerebellar ataxia with axonal neuropathy type 2 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 1 000 000 (France)

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-phe1812ile (accessed [today's date]).

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