Is AP3B1 p.Ala173= (c.519A>G) pathogenic?

AP3B1 p.Ala173= (c.519A>G) is classified Conflicting classifications of pathogenicity in AP3B1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-23). Very rare (popmax 0.01%, amr); Associated with Hermansky-Pudlak syndrome 2.

What condition is associated with AP3B1 p.Ala173= (c.519A>G)?

AP3B1 p.Ala173= (c.519A>G) is associated with Hermansky-Pudlak syndrome 2 (ClinVar).

How common is AP3B1 p.Ala173= (c.519A>G) in the general population?

AP3B1 p.Ala173= (c.519A>G) is very rare (popmax 0.01%, amr) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

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

AP3B1 p.Ala173=

c.519A>G · rs747459337 · VCV354250

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

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 -2.5	GERP -5.5
Overall
CADD	5.475	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/60,008 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00316% 51/1,613,478 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,001
Remaining individualsnot grpmax-eligible	0.0048%	20,819
European (non-Finnish)	0.00339%	29,492
Finnishnot grpmax-eligible	0.00156%	64,002
African / African-American	0.00134%	74,906

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.Ala173=
Coding: c.519A>G
MANE Select: NM_003664
dbSNP: rs747459337
Type: single nucleotide variant
Location: chr5:78227389 (GRCh38)
Gene constraint: LOEUF 0.59 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.85 · 5 PDB

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

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-ala173 (accessed [today's date]).

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