Is ITGA3 p.Leu453Pro (c.1358T>C) pathogenic?

ITGA3 p.Leu453Pro (c.1358T>C) is classified Uncertain significance in ITGA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-01). AlphaMissense: likely pathogenic (0.5953); Very rare (popmax 0.00329%, sas); Associated with epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome.

How common is ITGA3 p.Leu453Pro (c.1358T>C) in the general population?

ITGA3 p.Leu453Pro (c.1358T>C) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about ITGA3 p.Leu453Pro (c.1358T>C)?

AlphaMissense predicts likely pathogenic (score 0.5953) — an in-silico prediction, not a clinical call.

ITGA3 p.Leu453Pro

Q: What condition is associated with ITGA3 p.Leu453Pro (c.1358T>C)?

ITGA3 p.Leu453Pro (c.1358T>C) is associated with epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome (ClinVar).

Q: How is Interstitial lung disease-nephrotic syndrome-epidermolysis bullosa syndrome inherited?

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

c.1358T>C · VCV3582255

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5953 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome

Computational evidence

Protein change
AlphaMissense	0.5953	likely pathogenic
REVEL	0.77	pathogenic-leaning
SaProt	LLR -13.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 14 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,080 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00031% 5/1,614,048 alleles · very rare exomes 4/1,461,812 · genomes 1/152,236 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,360
Remaining individualsnot grpmax-eligible	0.0032%	31,243

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: ITGA3
Protein: p.Leu453Pro
Coding: c.1358T>C
MANE Select: NM_002204
Type: single nucleotide variant
Location: chr17:50074256 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.88

Full ITGA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Interstitial lung disease-nephrotic syndrome-epidermolysis bullosa syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ITGA3 c.2070+1G>A Pathogenic ★★ same condition
ITGA3 p.Arg274Gln Likely pathogenic ★★ ⚠ same condition
ITGA3 p.Arg875Ter Likely pathogenic ★★ same condition
ITGA3 c.*48G>A Uncertain significance ★★ same condition
ITGA3 c.*96G>A Uncertain significance ★★ same condition
ITGA3 p.Ala1026Val Uncertain significance ★★ ⚠ same condition
ITGA3 p.Ala1035Val Uncertain significance ★★ ⚠ same condition
ITGA3 p.Arg156Trp Uncertain significance ★★ ⚠ 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/itga3-p-leu453pro (accessed [today's date]).

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