Is AP3B1 p.Arg65Trp (c.193C>T) pathogenic?

AP3B1 p.Arg65Trp (c.193C>T) is classified Uncertain significance in AP3B1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-10-07). AlphaMissense: likely pathogenic (0.8172); Ultra-rare (popmax 0.0331%, mid); Associated with Hermansky-Pudlak syndrome 2.

What condition is associated with AP3B1 p.Arg65Trp (c.193C>T)?

AP3B1 p.Arg65Trp (c.193C>T) is associated with Hermansky-Pudlak syndrome 2 (ClinVar).

How common is AP3B1 p.Arg65Trp (c.193C>T) in the general population?

AP3B1 p.Arg65Trp (c.193C>T) is ultra-rare (popmax 0.0331%, mid) (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.Arg65Trp (c.193C>T)?

AlphaMissense predicts likely pathogenic (score 0.8172) — an in-silico prediction, not a clinical call.

AP3B1 p.Arg65Trp

c.193C>T · rs758616866 · VCV1305952

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8172 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Hermansky-Pudlak syndrome 2

Computational evidence

Protein change
AlphaMissense	0.8172	likely pathogenic
REVEL	0.347	indeterminate
SaProt	LLR -14.24	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP -0.52, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 27 kb · p 0.56 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0331% Middle Eastern · 2/6,044 alleles

Filtering AF 0.00583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00313%

Overall 0.00286% 46/1,609,390 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0331%	3,022
South Asian	0.00881%	11,346
Finnishnot grpmax-eligible	0.00473%	21,161
European (non-Finnish)	0.00255%	39,237
East Asian	0.00224%	44,668
Remaining individualsnot grpmax-eligible	0.00161%	62,280
African / African-American	0.00134%	74,782

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.Arg65Trp
Coding: c.193C>T
MANE Select: NM_003664
dbSNP: rs758616866
Type: single nucleotide variant
Location: chr5:78267531 (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.Arg65Gln 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-arg65trp (accessed [today's date]).

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