Is COL4A4 p.Leu519fs (c.1554del) pathogenic?

COL4A4 p.Leu519fs (c.1554del) is classified Likely pathogenic in COL4A4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-29). Absent from gnomAD; Associated with autosomal recessive Alport syndrome.

What condition is associated with COL4A4 p.Leu519fs (c.1554del)?

COL4A4 p.Leu519fs (c.1554del) is associated with autosomal recessive Alport syndrome, hematuria, benign familial, 1 (ClinVar).

How common is COL4A4 p.Leu519fs (c.1554del) in the general population?

COL4A4 p.Leu519fs (c.1554del) is absent from gnomAD (gnomAD).

How is Alport syndrome inherited?

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

COL4A4 p.Leu519fs

c.1554del · rs2059734968 · VCV1725417

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

autosomal recessive Alport syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 22 of 48
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.2	GERP -2.6

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: COL4A4
Protein: p.Leu519fs
Coding: c.1554del
MANE Select: NM_000092
dbSNP: rs2059734968
Type: Deletion
Location: chr2:227088722 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 519: the 'triple-helical region' region; the 'disordered' region

Full COL4A4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive Alport syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hematuria, benign familial, 1

For Alport syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked dominant
Onset: Adolescent, Adult, Childhood, Elderly

Similar variants

COL4A4 c.1321_1369+3del Pathogenic/Likely pathogenic ★★ same condition
COL4A4 c.2385del Pathogenic/Likely pathogenic ★★ same condition
COL4A4 c.327+1_327+5del Likely pathogenic ★★ same condition
COL4A4 c.4091-8_4092del Likely pathogenic ★★ same condition
COL4A4 c.914_930+29del Pathogenic/Likely pathogenic ★★ same condition
COL4A4 p.Ala1573fs Pathogenic/Likely pathogenic ★★ same condition
COL4A4 p.Ala793fs Pathogenic/Likely pathogenic ★★ same condition
COL4A4 p.Arg877_Gly888del 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/col4a4-p-leu519fs (accessed [today's date]).

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