# NM_003764.4(STX11):c.554dup (p.Trp186fs)

https://sugi.bio/variant/stx11-p-trp186fs

## Summary

**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.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1317576992 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0183%, amr)

## For patients & families {#patients}

This is a change in the STX11 gene that is considered disease-causing, submitted by 2 submitters, and is linked to familial hemophagocytic lymphohistiocytosis 4.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Infancy |
| Prevalence | 1-9 / 100 000 (Sweden) |
| Diagnostic panels | STX11 is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Familial hemophagocytic lymphohistiocytosis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Thrombocytopenia — Very frequent (99-80%)
- Anemia — Very frequent (99-80%)
- Fever — Very frequent (99-80%)
- Elevated circulating hepatic transaminase concentration — Very frequent (99-80%)
- Immune dysregulation — Very frequent (99-80%)
- Hypoalbuminemia — Very frequent (99-80%)
- Increased circulating ferritin concentration — Very frequent (99-80%)
- Abnormality of serum cytokine level — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009929/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [STX11](https://sugi.bio/atlas/gene/STX11/) |
| Protein change (HGVS p.) | p.Trp186fs |
| Coding change (HGVS c.) | c.554dup |
| MANE Select transcript | [NM_003764](https://www.ncbi.nlm.nih.gov/nuccore/NM_003764) |
| dbSNP | [rs1317576992](https://www.ncbi.nlm.nih.gov/snp/rs1317576992/) |
| Variant type | Duplication |
| Location | chr6:144187179-144187180 (GRCh38) |
| ClinVar | [VCV1686235](https://www.ncbi.nlm.nih.gov/clinvar/variation/1686235/) |

**All HGVS expressions:** `LRG_113:g.41665dup`, `LRG_113t1:c.554dup`, `NC_000006.11:g.144508318dup`, `NC_000006.12:g.144187181dup`, `NG_007613.1:g.41665dup`, `NM_003764.4:c.554dup`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.091, GERP 0.56, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.502, pLI 3.5849e-08. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (2 of 2)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 28.5**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0183%** (amr) · FAF95 0.0102% · FAF99 0.00785% · 11/59,984 in the highest group · 11/1,613,364 alleles overall — ultra-rare (popmax 0.0183%, amr).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**STX11** population constraint: LOEUF 1.502, pLI 3.5849e-08, missense-Z -0.24507. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **familial hemophagocytic lymphohistiocytosis 4** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 79.08, 25% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of STX11 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** STX11's established molecular role includes SNAP receptor activity.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** SNAP receptor activity.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-04-30.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mendelics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-30 |

## Associated conditions {#conditions}

[familial hemophagocytic lymphohistiocytosis 4](https://sugi.bio/atlas/disease/familial-hemophagocytic-lymphohistiocytosis-4/).

**Reported phenotype names (ClinVar):** Familial hemophagocytic lymphohistiocytosis 4, STX11-Related Familial Hemophagocytic Lymphohistiocytosis (STX11-fHLH).

## Similar variants {#similar}

Related STX11 variant pages (same residue, condition, or type): [STX11 p.Trp186Cys](/variant/stx11-p-trp186cys), [STX11 p.Arg216fs](/variant/stx11-p-arg216fs), [STX11 p.His118delinsArgGlyTer](/variant/stx11-p-his118delinsargglyter), [STX11 p.Ser190fs](/variant/stx11-p-ser190fs), [STX11 p.Asp53fs](/variant/stx11-p-asp53fs), [STX11 p.Gln131Ter](/variant/stx11-p-gln131ter), [STX11 p.Gln162Ter](/variant/stx11-p-gln162ter), [STX11 p.Glu25Ter](/variant/stx11-p-glu25ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1686235). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*