Is ITGB4 p.Pro253= (c.759G>A) pathogenic?

ITGB4 p.Pro253= (c.759G>A) is classified Conflicting classifications of pathogenicity in ITGB4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.02%, amr); Associated with junctional epidermolysis bullosa with pyloric atresia.

What condition is associated with ITGB4 p.Pro253= (c.759G>A)?

ITGB4 p.Pro253= (c.759G>A) is associated with junctional epidermolysis bullosa with pyloric atresia (ClinVar).

How common is ITGB4 p.Pro253= (c.759G>A) in the general population?

ITGB4 p.Pro253= (c.759G>A) is ultra-rare (popmax 0.02%, amr) (gnomAD).

ITGB4 p.Pro253=

Q: How is Junctional epidermolysis bullosa with pyloric atresia inherited?

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

c.759G>A · rs776214034 · VCV890954

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Conditions

junctional epidermolysis bullosa with pyloric atresia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP -10
Overall
CADD	5.631	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% Admixed American · 12/60,000 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00787% 127/1,612,744 alleles · ultra-rare exomes 104/1,460,550 · genomes 23/152,194 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.43%	70
Ashkenazi Jewishnot grpmax-eligible	0.176%	569
Admixed Americangrpmax	0.02%	5,000
Remaining individualsnot grpmax-eligible	0.00801%	12,490
European (non-Finnish)	0.00339%	29,498
South Asian	0.00329%	30,355
African / African-American	0.00267%	37,458

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ITGB4
Protein: p.Pro253=
Coding: c.759G>A
MANE Select: NM_000213
dbSNP: rs776214034
Type: single nucleotide variant
Location: chr17:75730261 (GRCh38)
Gene constraint: LOEUF 0.86 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.04 · 13 PDB
Residue 253: the vwfa domain

Full ITGB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

junctional epidermolysis bullosa with pyloric atresia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Junctional epidermolysis bullosa with pyloric atresia (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal

Similar variants

ITGB4 p.Pro253Leu Uncertain significance ★ ⚠ same residue
ITGB4 c.2254+1G>T Pathogenic/Likely pathogenic ★★ same condition
ITGB4 c.2550+1G>A Pathogenic/Likely pathogenic ★★ same condition
ITGB4 c.2633+1G>A Pathogenic/Likely pathogenic ★★ same condition
ITGB4 c.2783-2A>G Pathogenic/Likely pathogenic ★★ same condition
ITGB4 c.3793+1G>A Pathogenic ★★ same condition
ITGB4 p.Ala620= Pathogenic/Likely pathogenic ★★ same condition
ITGB4 p.Arg1225His Pathogenic/Likely 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/itgb4-p-pro253 (accessed [today's date]).

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