Is ITGA3 p.Pro681Ala (c.2041C>G) pathogenic?

ITGA3 p.Pro681Ala (c.2041C>G) is classified Uncertain significance in ITGA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-18). AlphaMissense: likely benign (0.081); Very rare (popmax 8.63e-05%, nfe); Associated with epidermolysis bullosa, junctional 7, with interstitial lung disease and nephrotic syndrome.

How common is ITGA3 p.Pro681Ala (c.2041C>G) in the general population?

ITGA3 p.Pro681Ala (c.2041C>G) is very rare (popmax 8.63e-05%, nfe) (gnomAD).

What do computational predictors say about ITGA3 p.Pro681Ala (c.2041C>G)?

AlphaMissense predicts likely benign (score 0.081) — an in-silico prediction, not a clinical call.

ITGA3 p.Pro681Ala

Q: What condition is associated with ITGA3 p.Pro681Ala (c.2041C>G)?

ITGA3 p.Pro681Ala (c.2041C>G) 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.2041C>G · VCV3582271

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.081 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.63e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.081	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -8.20	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 0.001	GERP -1.5
Regional constraint	o/e 0.84	unconstrained · MANE · 14 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	13.29	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 8.63e-05% European (non-Finnish) · 1/1,158,982 alleles

Overall 6.34e-05% 1/1,577,442 alleles · very rare exomes 1/1,425,348 · genomes 0/152,094 · joint denominator

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.Pro681Ala
Coding: c.2041C>G
MANE Select: NM_002204
Type: single nucleotide variant
Location: chr17:50077092 (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-pro681ala (accessed [today's date]).

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