Is AP3B1 p.Cys448Arg (c.1342T>C) pathogenic?

AP3B1 p.Cys448Arg (c.1342T>C) is classified Uncertain significance in AP3B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-12). AlphaMissense: ambiguous (0.3847); Very rare (popmax 0.00329%, sas); Associated with Hermansky-Pudlak syndrome 2.

What condition is associated with AP3B1 p.Cys448Arg (c.1342T>C)?

AP3B1 p.Cys448Arg (c.1342T>C) is associated with Hermansky-Pudlak syndrome 2 (ClinVar).

How common is AP3B1 p.Cys448Arg (c.1342T>C) in the general population?

AP3B1 p.Cys448Arg (c.1342T>C) is very rare (popmax 0.00329%, sas) (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 AP3B1 p.Cys448Arg (c.1342T>C)?

AlphaMissense predicts ambiguous (score 0.3847) — an in-silico prediction, not a clinical call.

AP3B1 p.Cys448Arg

c.1342T>C · rs768670539 · VCV2097506

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3847 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Hermansky-Pudlak syndrome 2

Computational evidence

Protein change
AlphaMissense	0.3847	ambiguous
REVEL	0.139	moderately benign-leaning
SaProt	LLR -3.33	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 213 kb · p 0.0039 · regional, not allelic
Overall
CADD	23.0	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 0.00329% South Asian · 3/91,084 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000205% 3/1,461,716 alleles · very rare

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.Cys448Arg
Coding: c.1342T>C
MANE Select: NM_003664
dbSNP: rs768670539
Type: single nucleotide variant
Location: chr5:78162840 (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 p.Cys448Tyr Uncertain significance ★★ ⚠ same residue
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

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-cys448arg (accessed [today's date]).

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