Is STXBP2 p.Phe249= (c.747C>T) pathogenic?

STXBP2 p.Phe249= (c.747C>T) is classified Likely benign in STXBP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-02). Very rare (popmax 0.00102%, nfe); Associated with familial hemophagocytic lymphohistiocytosis 5.

What condition is associated with STXBP2 p.Phe249= (c.747C>T)?

STXBP2 p.Phe249= (c.747C>T) is associated with familial hemophagocytic lymphohistiocytosis 5 (ClinVar).

How common is STXBP2 p.Phe249= (c.747C>T) in the general population?

STXBP2 p.Phe249= (c.747C>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

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

STXBP2 p.Phe249=

c.747C>T · rs772393674 · VCV538157

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Conditions

familial hemophagocytic lymphohistiocytosis 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -3.4, phastCons 1
Overall
CADD	12.37	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00102% European (non-Finnish) · 12/1,180,030 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000743% 12/1,614,054 alleles · very rare exomes 6/1,461,880 · genomes 6/152,174 · 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: STXBP2
Protein: p.Phe249=
Coding: c.747C>T
MANE Select: NM_006949
dbSNP: rs772393674
Type: single nucleotide variant
Location: chr19:7642286 (GRCh38)
Gene constraint: LOEUF 0.874 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.41 · 1 PDB
Residue 249: an α-helix

Full STXBP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial hemophagocytic lymphohistiocytosis 5 — 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

STXBP2 p.Phe249Ser Uncertain significance ★ ⚠ same residue
STXBP2 c.1107+1G>C Likely pathogenic ★★ same condition
STXBP2 c.1247-1G>C Pathogenic ★★ same condition
STXBP2 c.1356+1G>T Likely pathogenic ★★ same condition
STXBP2 c.169+2T>G Pathogenic/Likely pathogenic ★★ same condition
STXBP2 c.247-2A>C Likely pathogenic ★★ same condition
STXBP2 c.247-2A>G Likely pathogenic ★★ same condition
STXBP2 c.87+2T>C Pathogenic/Likely 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/stxbp2-p-phe249 (accessed [today's date]).

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