Is ITGB2 p.Arg253Ser (c.757C>A) pathogenic?

ITGB2 p.Arg253Ser (c.757C>A) is classified Uncertain significance in ITGB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-31). AlphaMissense: ambiguous (0.4956); Very rare (popmax 0.0022%, sas); Associated with leukocyte adhesion deficiency 1.

What condition is associated with ITGB2 p.Arg253Ser (c.757C>A)?

ITGB2 p.Arg253Ser (c.757C>A) is associated with leukocyte adhesion deficiency 1 (ClinVar).

How common is ITGB2 p.Arg253Ser (c.757C>A) in the general population?

ITGB2 p.Arg253Ser (c.757C>A) is very rare (popmax 0.0022%, sas) (gnomAD).

How is Leukocyte adhesion deficiency inherited?

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

What do computational predictors say about ITGB2 p.Arg253Ser (c.757C>A)?

AlphaMissense predicts ambiguous (score 0.4956) — an in-silico prediction, not a clinical call.

ITGB2 p.Arg253Ser

c.757C>A · rs772607011 · VCV1460972

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4956 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

leukocyte adhesion deficiency 1

Computational evidence

Protein change
AlphaMissense	0.4956	ambiguous
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -7.43	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP -3.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 24 kb · p 0.00051 · regional, not allelic
Overall
CADD	25.0	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 0.0022% South Asian · 2/91,074 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000342% 5/1,461,086 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,537
European (non-Finnish)	0.000254%	393,312

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: ITGB2
Protein: p.Arg253Ser
Coding: c.757C>A
MANE Select: NM_000211
dbSNP: rs772607011
Type: single nucleotide variant
Location: chr21:44900460 (GRCh38)
Gene constraint: LOEUF 0.81 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.02 · 29 PDB
Residue 253: a disulfide bond; the vwfa domain

Full ITGB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

leukocyte adhesion deficiency 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Leukocyte adhesion deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

ITGB2 p.Arg253Cys Uncertain significance ★★ ⚠ same residue
ITGB2 p.Arg253His Uncertain significance ★ ⚠ same residue
ITGB2 c.741+1G>A Pathogenic/Likely pathogenic ★★ same condition
ITGB2 c.897+1G>A Pathogenic/Likely pathogenic ★★ same condition
ITGB2 p.Ala239Thr Pathogenic/Likely pathogenic ★★ same condition
ITGB2 p.Ala270Val Likely pathogenic ★★ same condition
ITGB2 p.Arg108Ter Pathogenic/Likely pathogenic ★★ same condition
ITGB2 p.Arg188Ter 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/itgb2-p-arg253ser (accessed [today's date]).

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