Is BLOC1S6 p.Arg66= (c.198A>G) pathogenic?

BLOC1S6 p.Arg66= (c.198A>G) is classified Likely benign in BLOC1S6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-26). Ultra-rare (popmax 0.0495%, mid); Associated with Hermansky-Pudlak syndrome 9.

What condition is associated with BLOC1S6 p.Arg66= (c.198A>G)?

BLOC1S6 p.Arg66= (c.198A>G) is associated with Hermansky-Pudlak syndrome 9 (ClinVar).

How common is BLOC1S6 p.Arg66= (c.198A>G) in the general population?

BLOC1S6 p.Arg66= (c.198A>G) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

How is Familial hemophagocytic lymphohistiocytosis inherited?

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

BLOC1S6 p.Arg66=

c.198A>G · rs1329457663 · VCV1116731

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Conditions

Hermansky-Pudlak syndrome 9

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 3.1	GERP 0.95, phastCons 1
Overall
CADD	9.232	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% Middle Eastern · 3/6,062 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.000372% 6/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0032%	31,255
European (non-Finnish)	8.47e-05%	1,180,027

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: BLOC1S6
Protein: p.Arg66=
Coding: c.198A>G
MANE Select: NM_012388
dbSNP: rs1329457663
Type: single nucleotide variant
Location: chr15:45592250 (GRCh38)
Gene constraint: LOEUF 1.5 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.10

Full BLOC1S6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hermansky-Pudlak syndrome 9 — 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

BLOC1S6 p.Arg66Gly Uncertain significance ★ ⚠ same residue
BLOC1S6 p.Gln78Ter Pathogenic ★★ same condition
BLOC1S6 p.Ser67Ter Pathogenic/Likely pathogenic ★★ same condition
BLOC1S6 p.Arg154Gln Uncertain significance ★★ ⚠ same condition
BLOC1S6 p.Arg154Ter Uncertain significance ★★ same condition
BLOC1S6 p.Arg15Trp Uncertain significance ★★ ⚠ same condition
BLOC1S6 p.Arg167Ser Uncertain significance ★★ ⚠ same condition
BLOC1S6 p.Asp35Asn 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/bloc1s6-p-arg66 (accessed [today's date]).

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