Is STX11 p.Trp186fs (c.554dup) pathogenic?

STX11 p.Trp186fs (c.554dup) is classified Pathogenic in STX11 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-30). Ultra-rare (popmax 0.0183%, amr); Associated with familial hemophagocytic lymphohistiocytosis 4.

What condition is associated with STX11 p.Trp186fs (c.554dup)?

STX11 p.Trp186fs (c.554dup) is associated with familial hemophagocytic lymphohistiocytosis 4 (ClinVar).

How common is STX11 p.Trp186fs (c.554dup) in the general population?

STX11 p.Trp186fs (c.554dup) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

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

STX11 p.Trp186fs

c.554dup · rs1317576992 · VCV1686235

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Conditions

familial hemophagocytic lymphohistiocytosis 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.1	GERP 0.56, phastCons 1
Overall
CADD	28.5	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 0.0183% Admixed American · 11/59,984 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.000682% 11/1,613,364 alleles · ultra-rare exomes 7/1,461,658 · genomes 4/151,706 · 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: STX11
Protein: p.Trp186fs
Coding: c.554dup
MANE Select: NM_003764
dbSNP: rs1317576992
Type: Duplication
Location: chr6:144187179 (GRCh38)
Gene constraint: LOEUF 1.502 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.08

Full STX11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial hemophagocytic lymphohistiocytosis 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial hemophagocytic lymphohistiocytosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Infancy
Prevalence: 1-9 / 100 000 (Sweden)

Similar variants

STX11 p.Trp186Cys Uncertain significance ★ ⚠ same residue
STX11 p.Arg216fs Pathogenic/Likely pathogenic ★★ same condition
STX11 p.His118delinsArgGlyTer Likely pathogenic ★ same condition
STX11 p.Ser190fs Likely pathogenic ★ same condition
STX11 p.Asp53fs Likely pathogenic ★★ same condition
STX11 p.Gln131Ter Pathogenic/Likely pathogenic ★★ same condition
STX11 p.Gln162Ter Pathogenic/Likely pathogenic ★★ same condition
STX11 p.Glu25Ter 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/stx11-p-trp186fs (accessed [today's date]).

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