Is STXBP2 p.Pro69Ala (c.205C>G) pathogenic?

STXBP2 p.Pro69Ala (c.205C>G) is classified Uncertain significance in STXBP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-28). AlphaMissense: likely benign (0.1497); Very rare (popmax 0.005%, amr); Associated with familial hemophagocytic lymphohistiocytosis 5.

What condition is associated with STXBP2 p.Pro69Ala (c.205C>G)?

STXBP2 p.Pro69Ala (c.205C>G) is associated with familial hemophagocytic lymphohistiocytosis 5 (ClinVar).

How common is STXBP2 p.Pro69Ala (c.205C>G) in the general population?

STXBP2 p.Pro69Ala (c.205C>G) is very rare (popmax 0.005%, amr) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

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

What do computational predictors say about STXBP2 p.Pro69Ala (c.205C>G)?

AlphaMissense predicts likely benign (score 0.1497) — an in-silico prediction, not a clinical call.

STXBP2 p.Pro69Ala

c.205C>G · rs532380776 · VCV1489556

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1497 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial hemophagocytic lymphohistiocytosis 5

Computational evidence

Protein change
AlphaMissense	0.1497	likely benign
REVEL	0.437	indeterminate
SaProt	LLR -8.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 11 kb · p 0.0002 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,008 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00155% 25/1,613,796 alleles · very rare exomes 20/1,461,468 · genomes 5/152,328 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,003
European (non-Finnish)	0.00178%	56,191
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Pro69Ala
Coding: c.205C>G
MANE Select: NM_006949
dbSNP: rs532380776
Type: single nucleotide variant
Location: chr19:7639766 (GRCh38)
Gene constraint: LOEUF 0.874 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.41 · 1 PDB

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.Pro69His 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-pro69ala (accessed [today's date]).

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