Is SETX p.Ile81fs (c.243del) pathogenic?

SETX p.Ile81fs (c.243del) is classified Pathogenic in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2017-09-19). Very rare (popmax 0.004%, afr).

How common is SETX p.Ile81fs (c.243del) in the general population?

SETX p.Ile81fs (c.243del) is very rare (popmax 0.004%, afr) (gnomAD).

SETX p.Ile81fs

c.243del · rs1455336434 · VCV452281

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 4 of 26
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 0.99
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,912 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,690 alleles · very rare exomes 1/1,461,540 · genomes 2/152,150 · 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.Ile81fs
Coding: c.243del
MANE Select: NM_015046
dbSNP: rs1455336434
Type: Deletion
Location: chr9:132346406 (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

Similar variants

SETX p.Ile81Val Conflicting classifications of pathogenicity ★ ⚠ same residue
SETX c.6843-3_6843-1del Likely pathogenic ★★ same type
SETX c.6848_6851del Pathogenic ★★ same type
SETX p.Asp2332fs Pathogenic/Likely pathogenic ★★ same type
SETX p.Gln1864fs Pathogenic/Likely pathogenic ★★ same type
SETX p.Lys796fs Pathogenic ★★ same type
SETX p.Thr1755fs Pathogenic ★★ same type
SETX p.Arg2529fs Uncertain significance ★★ same type

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-ile81fs (accessed [today's date]).

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