Is ITGB4 p.Ser1069Pro (c.3205T>C) pathogenic?

ITGB4 p.Ser1069Pro (c.3205T>C) is classified Conflicting classifications of pathogenicity in ITGB4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-22). AlphaMissense: likely benign (0.2898); Ultra-rare (popmax 0.025%, amr); Associated with Inborn genetic diseases.

What condition is associated with ITGB4 p.Ser1069Pro (c.3205T>C)?

ITGB4 p.Ser1069Pro (c.3205T>C) is associated with Inborn genetic diseases, junctional epidermolysis bullosa with pyloric atresia, epidermolysis bullosa, junctional 5A, intermediate (ClinVar).

How common is ITGB4 p.Ser1069Pro (c.3205T>C) in the general population?

ITGB4 p.Ser1069Pro (c.3205T>C) is ultra-rare (popmax 0.025%, amr) (gnomAD).

What do computational predictors say about ITGB4 p.Ser1069Pro (c.3205T>C)?

AlphaMissense predicts likely benign (score 0.2898) — an in-silico prediction, not a clinical call.

ITGB4 p.Ser1069Pro

c.3205T>C · rs530916890 · VCV888919

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2898 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2898	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -5.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	phastCons 0.99
Regional constraint	o/e 0.89	unconstrained · MANE · 33 kb · p 1e-07 · regional, not allelic
Overall
CADD	21.1	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 0.025% Admixed American · 15/59,964 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00124% 20/1,613,144 alleles · ultra-rare exomes 9/1,461,002 · genomes 11/152,142 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	3,998
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
Remaining individualsnot grpmax-eligible	0.0016%	62,474
African / African-American	0.00133%	74,974
European (non-Finnish)	0.00017%	589,971

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.Ser1069Pro
Coding: c.3205T>C
MANE Select: NM_000213
dbSNP: rs530916890
Type: single nucleotide variant
Location: chr17:75748934 (GRCh38)
Gene constraint: LOEUF 0.86 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.04 · 13 PDB
Residue 1069: the calx-beta domain; a modified residue (phosphoserine)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: junctional epidermolysis bullosa with pyloric atresia epidermolysis bullosa, junctional 5A, intermediate

Similar variants

ITGB4 p.Ser1069= Likely benign ★ 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-ser1069pro (accessed [today's date]).

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