Is SETX p.Ile614Val (c.1840A>G) pathogenic?

SETX p.Ile614Val (c.1840A>G) is classified Uncertain significance in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-01). AlphaMissense: likely benign (0.0734); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary spastic paraplegia.

What condition is associated with SETX p.Ile614Val (c.1840A>G)?

SETX p.Ile614Val (c.1840A>G) is associated with hereditary spastic paraplegia (ClinVar).

How common is SETX p.Ile614Val (c.1840A>G) in the general population?

SETX p.Ile614Val (c.1840A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about SETX p.Ile614Val (c.1840A>G)?

AlphaMissense predicts likely benign (score 0.0734) — an in-silico prediction, not a clinical call.

SETX p.Ile614Val

c.1840A>G · rs1318709540 · VCV1344012

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0734 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.0734	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -5.97	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 -0.05	GERP -0.43
Regional constraint	o/e 1.13	unconstrained · MANE · 3,399 bp · p 2.4e-06 · regional, not allelic
Overall
CADD	7.576	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,996 alleles

Overall 6.2e-05% 1/1,614,112 alleles · very rare exomes 1/1,461,796 · genomes 0/152,316 · joint denominator

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.Ile614Val
Coding: c.1840A>G
MANE Select: NM_015046
dbSNP: rs1318709540
Type: single nucleotide variant
Location: chr9:132329758 (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

hereditary spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETX p.Ile614Thr Uncertain significance ★ ⚠ same residue
SETX p.Gly1011Arg Uncertain significance ★★ ⚠ same condition
SETX p.Ala1112= Benign/Likely benign ★★ same condition
SETX p.Ala1782= Benign/Likely benign ★★ same condition
SETX p.Arg20His Benign/Likely benign ★★ same condition
SETX p.Asn603Asp Benign/Likely benign ★★ same condition
SETX p.Asp2372Asn Benign/Likely benign ★★ ⚠ same condition
SETX p.Cys1554Gly Benign/Likely benign ★★ ⚠ 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-ile614val (accessed [today's date]).

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