Is BLOC1S6 p.Ser97Pro (c.289T>C) pathogenic?

BLOC1S6 p.Ser97Pro (c.289T>C) is classified Uncertain significance in BLOC1S6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-07). AlphaMissense: likely pathogenic (0.6925); Absent from gnomAD v4.1; Associated with Hermansky-Pudlak syndrome 9.

What condition is associated with BLOC1S6 p.Ser97Pro (c.289T>C)?

BLOC1S6 p.Ser97Pro (c.289T>C) is associated with Hermansky-Pudlak syndrome 9 (ClinVar).

How common is BLOC1S6 p.Ser97Pro (c.289T>C) in the general population?

BLOC1S6 p.Ser97Pro (c.289T>C) is absent from gnomAD v4.1 (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 BLOC1S6 p.Ser97Pro (c.289T>C)?

AlphaMissense predicts likely pathogenic (score 0.6925) — an in-silico prediction, not a clinical call.

BLOC1S6 p.Ser97Pro

c.289T>C · rs1274935670 · VCV1513586

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6925 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,604,728)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hermansky-Pudlak syndrome 9

Computational evidence

Protein change
AlphaMissense	0.6925	likely pathogenic
REVEL	0.208	benign-leaning
SaProt	LLR -9.47	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 19 kb · p 0.13 · regional, not allelic
Overall
CADD	26.8	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

No allele count reported in gnomAD v4.1 (AN 1,604,728). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: BLOC1S6
Protein: p.Ser97Pro
Coding: c.289T>C
MANE Select: NM_012388
dbSNP: rs1274935670
Type: single nucleotide variant
Location: chr15:45603164 (GRCh38)
Gene constraint: LOEUF 1.5 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.10
Residue 97: a UniProt-annotated variant site (in hps9; reduces nk cell cytolytic activity; increases lamp1/cd107a and cd63 levels at the cell membrane)

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.Ser97Phe 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-ser97pro (accessed [today's date]).

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