Is ITGA2B p.Ala297Pro (c.889G>C) pathogenic?

ITGA2B p.Ala297Pro (c.889G>C) is classified Likely pathogenic in ITGA2B (ClinVar, Expert panel, 2 submitters; last evaluated 2024-09-05). AlphaMissense: likely pathogenic (0.964); Very rare (popmax 0.00439%, sas); Associated with Glanzmann thrombasthenia.

What condition is associated with ITGA2B p.Ala297Pro (c.889G>C)?

ITGA2B p.Ala297Pro (c.889G>C) is associated with Glanzmann thrombasthenia (ClinVar).

How common is ITGA2B p.Ala297Pro (c.889G>C) in the general population?

ITGA2B p.Ala297Pro (c.889G>C) is very rare (popmax 0.00439%, sas) (gnomAD).

How is Glanzmann thrombasthenia inherited?

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

What do computational predictors say about ITGA2B p.Ala297Pro (c.889G>C)?

AlphaMissense predicts likely pathogenic (score 0.964) — an in-silico prediction, not a clinical call.

ITGA2B p.Ala297Pro

c.889G>C · rs531610168 · VCV953005

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.964 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Glanzmann thrombasthenia

ClinGen expert panel — Platelet Disorders VCEP

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

PP4_Moderate PM2_Supporting PP1 PM3

Curation rationale (ClinGen, verbatim)

The NM_000419.4:c.889G>C variant that results in the Ala297Pro amino acid change is seen in one unpublished homozygous GT individual with mild mucocutaneous bleeding symptoms and lack of platelet aggregation in response to ADP, collagen, U46619, AA and TRAP, but normal response to ristocetin (PP4_moderate). As well as their affected homozygous sibling (PP1). A second homozygous individual has also been reported (PM3; PMID: 32089034). The variant is reported in gnomADv4.1 at a frequency of 0.00004392 (4/91080 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, based on the available evidence at this time, the variant is classified as likely pathogenic for GT. GT-specific criteria applied: PM2_Supporting, PM3, PP1, and PP4_Moderate.

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

Computational evidence

Protein change
AlphaMissense	0.964	likely pathogenic ✓ concordant with ClinVar · top 3% in ITGA2B
REVEL	0.369	indeterminate
SaProt	LLR -13.36	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 3.3	GERP 1.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 13 kb · p 0.0004 · regional, not allelic
Overall
CADD	22.1	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 0.00439% South Asian · 4/91,080 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000342% 5/1,461,142 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,770
European (non-Finnish)	8.48e-05%	1,179,922

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: ITGA2B
Protein: p.Ala297Pro
Coding: c.889G>C
MANE Select: NM_000419
dbSNP: rs531610168
Type: single nucleotide variant
Location: chr17:44384313 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.00 · 80 PDB
Residue 297: a β-strand

Full ITGA2B 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

ITGA2B p.Ala297Thr Uncertain significance ★ ⚠ same residue
ITGA2B c.1210+105A>G Likely pathogenic ★★★ same condition
ITGA2B c.1210+5G>A Likely pathogenic ★★★ same condition
ITGA2B c.1211-1G>C Likely pathogenic ★★★ same condition
ITGA2B c.1544+1G>A Pathogenic ★★★ same condition
ITGA2B c.1545-1G>A Pathogenic ★★★ same condition
ITGA2B c.1600+1G>A Pathogenic ★★★ same condition
ITGA2B c.1752+2T>C 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/itga2b-p-ala297pro (accessed [today's date]).

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