Is ITGB3 p.Pro433= (c.1299C>T) pathogenic?

ITGB3 p.Pro433= (c.1299C>T) is classified Likely benign in ITGB3 (ClinVar, Expert panel, 5 submitters; last evaluated 2023-12-19). Rare (popmax 0.297%, mid); Associated with Glanzmann thrombasthenia.

What condition is associated with ITGB3 p.Pro433= (c.1299C>T)?

ITGB3 p.Pro433= (c.1299C>T) is associated with Glanzmann thrombasthenia (ClinVar).

How common is ITGB3 p.Pro433= (c.1299C>T) in the general population?

ITGB3 p.Pro433= (c.1299C>T) is rare (popmax 0.297%, mid) (gnomAD).

How is Glanzmann thrombasthenia inherited?

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

ITGB3 p.Pro433=

c.1299C>T · rs200857868 · VCV323866

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.297%, mid)

Conditions

Glanzmann thrombasthenia

ClinGen expert panel — Platelet Disorders VCEP

Likely Benign for Glanzmann thrombasthenia. Applied ACMG criteria (verbatim):

BS1 BP7 BP4

Curation rationale (ClinGen, verbatim)

The NM_000212.2(ITGB3):c.1299C>T (p.Pro433=) synonymous variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population and has been reported in the literature in a healthy cohort (PMID: 27965976) but has not been reported in a Glanzmann thrombasthenia patient. In gnomAD v4.0.0 the minor allele frequency is 0.001910 (174/91086 alleles) in the South Asian population, which meets the BS1 threshold (>0.00158). Splicing prediction algorithms (MaxEntScan, HSF, and SpliceAI) predict no impact on splicing (BP4) and the nucleotide is not highly conserved (phyloP score 0.129449; BP7). In summary this variant meets criteria to be classified as likely benign. GT-specific criteria applied: BS1, BP4 and BP7.

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

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 -0.81	GERP -2.9, phastCons 0.002
Overall
CADD	6.796	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.297% Middle Eastern · 18/6,062 alleles

Filtering AF 0.192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.159%

Overall 0.0469% 757/1,614,182 alleles · rare exomes 668/1,461,892 · genomes 89/152,290 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.297%	337
South Asian	0.191%	523
Admixed American	0.108%	923
Remaining individualsnot grpmax-eligible	0.0768%	1,302
European (non-Finnish)	0.0371%	2,694
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,922
African / African-American	0.012%	8,338

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: ITGB3
Protein: p.Pro433=
Coding: c.1299C>T
MANE Select: NM_000212
dbSNP: rs200857868
Type: single nucleotide variant
Location: chr17:47292177 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.19 · 125 PDB
Residue 433: a UniProt-annotated variant site (risk factor for fmait1; alloantigen mo(+))

Full ITGB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Glanzmann thrombasthenia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glanzmann thrombasthenia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ITGB3 p.Pro433Ala Uncertain significance ★★ ⚠ same residue
ITGB3 c.166-2A>G Pathogenic ★★★ same condition
ITGB3 c.1913+1G>A Pathogenic ★★★ same condition
ITGB3 c.1913+5G>T Likely pathogenic ★★★ same condition
ITGB3 c.2014+1G>A Pathogenic ★★★ same condition
ITGB3 c.2014+5G>A Likely pathogenic ★★★ same condition
ITGB3 c.2301+1G>C Pathogenic ★★★ same condition
ITGB3 c.361+1G>A Pathogenic ★★★ 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/itgb3-p-pro433 (accessed [today's date]).

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