Is STX11 p.Arg129Pro (c.386G>C) pathogenic?

STX11 p.Arg129Pro (c.386G>C) is classified Uncertain significance in STX11 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: likely pathogenic (0.876); Very rare (popmax 8.48e-05%, nfe); Associated with familial hemophagocytic lymphohistiocytosis 4.

What condition is associated with STX11 p.Arg129Pro (c.386G>C)?

STX11 p.Arg129Pro (c.386G>C) is associated with familial hemophagocytic lymphohistiocytosis 4 (ClinVar).

How common is STX11 p.Arg129Pro (c.386G>C) in the general population?

STX11 p.Arg129Pro (c.386G>C) is very rare (popmax 8.48e-05%, nfe) (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 STX11 p.Arg129Pro (c.386G>C)?

AlphaMissense predicts likely pathogenic (score 0.876) — an in-silico prediction, not a clinical call.

STX11 p.Arg129Pro

c.386G>C · rs1231989334 · VCV1951725

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.876 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hemophagocytic lymphohistiocytosis 4

Computational evidence

Protein change
AlphaMissense	0.876	likely pathogenic · top 7% in STX11
REVEL	0.14	moderately benign-leaning
SaProt	LLR -13.94	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.5	GERP -3.5
Regional constraint	o/e 1.08	unconstrained · MANE · 860 bp · p 0.11 · regional, not allelic
Overall
CADD	18.88	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,748 alleles

Overall 6.21e-05% 1/1,611,250 alleles · very rare exomes 1/1,458,888 · genomes 0/152,362 · 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.Arg129Pro
Coding: c.386G>C
MANE Select: NM_003764
dbSNP: rs1231989334
Type: single nucleotide variant
Location: chr6:144187013 (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.Arg129Trp Uncertain significance ★ ⚠ same residue
STX11 p.Arg129= Likely benign ★ same residue
STX11 p.Gln131Ter Pathogenic/Likely pathogenic ★★ same condition
STX11 p.Gln162Ter Pathogenic/Likely pathogenic ★★ same condition
STX11 p.Glu25Ter Pathogenic ★★ same condition
STX11 p.Leu58Pro Pathogenic ★★ same condition
STX11 p.Ser28Ter Pathogenic/Likely pathogenic ★★ same condition
STX11 p.Tyr132Ter 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/stx11-p-arg129pro (accessed [today's date]).

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