Is AP3B1 p.Leu396= (c.1186T>C) pathogenic?

AP3B1 p.Leu396= (c.1186T>C) is classified Benign/Likely benign in AP3B1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-06). Rare (popmax 0.175%, sas); Associated with Hermansky-Pudlak syndrome 2.

What condition is associated with AP3B1 p.Leu396= (c.1186T>C)?

AP3B1 p.Leu396= (c.1186T>C) is associated with Hermansky-Pudlak syndrome 2, autoinflammatory syndrome (ClinVar).

How common is AP3B1 p.Leu396= (c.1186T>C) in the general population?

AP3B1 p.Leu396= (c.1186T>C) is rare (popmax 0.175%, sas) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

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

AP3B1 p.Leu396=

c.1186T>C · rs574476271 · VCV1169673

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.175%, sas)

Conditions

Hermansky-Pudlak syndrome 2

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 3.4	GERP -2.1, phastCons 1
Overall
CADD	6.045	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.175% South Asian · 158/90,462 alleles

Filtering AF 0.152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.144%

Overall 0.0109% 176/1,607,832 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.175%	573
Middle Eastern	0.0665%	1,504
Remaining individualsnot grpmax-eligible	0.00963%	10,383
European (non-Finnish)	0.00068%	146,954

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: AP3B1
Protein: p.Leu396=
Coding: c.1186T>C
MANE Select: NM_003664
dbSNP: rs574476271
Type: single nucleotide variant
Location: chr5:78165654 (GRCh38)
Gene constraint: LOEUF 0.59 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.85 · 5 PDB
Residue 396: a UniProt-annotated variant site (in hps2)

Full AP3B1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hermansky-Pudlak syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autoinflammatory syndrome

For Familial hemophagocytic lymphohistiocytosis (Orphanet):

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

Similar variants

AP3B1 c.2078-1G>A Likely pathogenic ★★ same condition
AP3B1 c.280-2A>G Likely pathogenic ★★ same condition
AP3B1 p.Arg104Ter Pathogenic/Likely pathogenic ★★ same condition
AP3B1 p.Arg649Ter Pathogenic/Likely pathogenic ★★ same condition
AP3B1 c.128+4A>G Uncertain significance ★★ same condition
AP3B1 c.2077+6T>C Uncertain significance ★★ same condition
AP3B1 c.2809+4A>G Uncertain significance ★★ same condition
AP3B1 c.2992+3G>A Uncertain significance ★★ 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/ap3b1-p-leu396 (accessed [today's date]).

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