Is SETX p.Ser1848Ter (c.5543C>A) pathogenic?

SETX p.Ser1848Ter (c.5543C>A) is classified Likely pathogenic in SETX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-18). Very rare (popmax 0.00134%, afr).

How common is SETX p.Ser1848Ter (c.5543C>A) in the general population?

SETX p.Ser1848Ter (c.5543C>A) is very rare (popmax 0.00134%, afr) (gnomAD).

SETX p.Ser1848Ter

c.5543C>A · rs1844937854 · VCV1807016

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 12 of 26
Splicing
SpliceAI	Δ0.94	donor gain · deltas
Pangolin	Δ0.83	gain · loss 0.25 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.9	GERP 1.5, phastCons 1
Overall
CADD	56.0	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 0.00134% African / African-American · 1/74,878 alleles

Overall 6.2e-05% 1/1,613,386 alleles · very rare exomes 0/1,461,230 · genomes 1/152,156 · 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.Ser1848Ter
Coding: c.5543C>A
MANE Select: NM_015046
dbSNP: rs1844937854
Type: single nucleotide variant
Location: chr9:132300635 (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.Arg111Ter Pathogenic ★★ same type
SETX p.Arg1363Ter Pathogenic ★★ same type
SETX p.Arg1606Ter Pathogenic ★★ same type
SETX p.Arg1778Ter Pathogenic/Likely pathogenic ★★ same type
SETX p.Arg2098Ter Pathogenic ★★ same type
SETX p.Arg332Trp Pathogenic/Likely pathogenic ★★ same type
SETX p.Arg778Ter Pathogenic/Likely pathogenic ★★ same type
SETX p.Gln1695Ter Pathogenic/Likely pathogenic ★★ 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-ser1848ter (accessed [today's date]).

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