Is GP1BB p.Ala133Pro (c.397G>C) pathogenic?

GP1BB p.Ala133Pro (c.397G>C) is classified Pathogenic in GP1BB (ClinVar, No assertion criteria, 1 submitter; last evaluated 1997-04-01). AlphaMissense: likely benign (0.1038); Ultra-rare (popmax 0.0103%, eas); Associated with MACROTHROMBOCYTOPENIA, FAMILIAL, BERNARD-SOULIER TYPE.

What condition is associated with GP1BB p.Ala133Pro (c.397G>C)?

GP1BB p.Ala133Pro (c.397G>C) is associated with MACROTHROMBOCYTOPENIA, FAMILIAL, BERNARD-SOULIER TYPE (ClinVar).

How common is GP1BB p.Ala133Pro (c.397G>C) in the general population?

GP1BB p.Ala133Pro (c.397G>C) is ultra-rare (popmax 0.0103%, eas) (gnomAD).

What do computational predictors say about GP1BB p.Ala133Pro (c.397G>C)?

AlphaMissense predicts likely benign (score 0.1038) — an in-silico prediction, not a clinical call.

GP1BB p.Ala133Pro

c.397G>C · rs121909751 · VCV16039

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1038 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

MACROTHROMBOCYTOPENIA, FAMILIAL, BERNARD-SOULIER TYPE

ClinGen expert panel — Platelet Disorders VCEP

Likely Pathogenic for Bernard-Soulier syndrome. Applied ACMG criteria (verbatim):

PM2_Supporting PS3_Supporting PP1 PP4 PM3

Curation rationale (ClinGen, verbatim)

The missense variant NM_000407.5(GP1BB):c.397G>C (p.Ala133Pro) has a Grpmax Filtering allele frequency in gnomAD v4.1 is 0.00002722 (based on 3/29196 alleles) in the East Asian population, which is lower than the ClinGen PD VCEP threshold (<0.00006517; PM2_Supporting). At least one patient (Patient A.K. in PMID: 9116284) with this variant had aggregation absent for ristocetin and present for all other agonists and flow cytometry found the expression of GPIbα, the GPIb/IX complex, and GPIX were remarkably lower than the normal control. which is highly specific for Bernard-Soulier syndrome (PP4). Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. The patient is compound heterozygote has been reported with Tyr113Cys (provisionally classified Likely Pathogenic by PD VCEP) and Ala133Pro confirmed in trans from heterozygous parents (PMID: 9116284; PM3). There is segregation of this variant in 1 additional compound heterozygous BSS family member (PMID: 9116284; total 1pt, PP1). In transiently transfected CHO cells HA-GPIbβ was present on the cell surface but GPIX was not (PMID: 21908432). In transiently transfected CHO cells HA-GPIbβ was present on the cell surface around 20% but GPIX was absent (PMID: 21908432; PS3_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3_supporting, PM3, PM2_supporting, PP1, PP4.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.1038	likely benign ⚠ discordant with ClinVar
REVEL	0.496	indeterminate
SaProt	LLR -6.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.28	GERP -2.7, phastCons 0.58
Regional constraint	o/e 1.03	unconstrained · MANE · 891 bp · p 0.61 · regional, not allelic
Overall
CADD	15.58	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 0.0103% East Asian · 3/29,196 alleles

Filtering AF 0.00272% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00145%

Overall 0.000323% 4/1,240,022 alleles · ultra-rare exomes 4/1,088,936 · genomes 0/151,086 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0103%	9,732
European (non-Finnish)	0.0001%	995,937

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: GP1BB
Protein: p.Ala133Pro
Coding: c.397G>C
MANE Select: NM_000407
dbSNP: rs121909751
Type: single nucleotide variant
Location: chr22:19724240 (GRCh38)
Gene constraint: LOEUF 1.922 · pLI 0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.43 · 3 PDB
Residue 133: a UniProt-annotated variant site (in bss); the lrrct domain

Full GP1BB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MACROTHROMBOCYTOPENIA, FAMILIAL, BERNARD-SOULIER TYPE — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GP1BB p.Ala133= Likely benign ★ same residue
GP1BB p.Asn89Asp Likely pathogenic ★★★ same type
GP1BB p.Asn89Thr Likely pathogenic ★★★ same type
GP1BB p.Cys141Ter Pathogenic ★★★ same type
GP1BB p.Cys147Ser Likely pathogenic ★★★ ⚠ same type
GP1BB p.Cys30Tyr Likely pathogenic ★★★ same type
GP1BB p.Cys32Ter Likely pathogenic ★★★ same type
GP1BB p.Glu136Ter Likely pathogenic ★★★ same type

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/gp1bb-p-ala133pro (accessed [today's date]).

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