Is COL4A4 p.Pro228fs (c.678_682dup) pathogenic?

COL4A4 p.Pro228fs (c.678682dup) is classified Pathogenic in COL4A4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-08). Absent from gnomAD; Associated with autosomal dominant Alport syndrome.

What condition is associated with COL4A4 p.Pro228fs (c.678_682dup)?

COL4A4 p.Pro228fs (c.678_682dup) is associated with autosomal dominant Alport syndrome (ClinVar).

How common is COL4A4 p.Pro228fs (c.678_682dup) in the general population?

COL4A4 p.Pro228fs (c.678_682dup) 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.Pro228fs

c.678_682dup · rs1576571835 · VCV830016

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

autosomal dominant 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 11 of 48
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1

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.Pro228fs
Coding: c.678_682dup
MANE Select: NM_000092
dbSNP: rs1576571835
Type: Duplication
Location: chr2:227108843 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 228: 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 dominant Alport syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Alport syndrome (Orphanet):

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

Similar variants

COL4A4 p.Cys1588fs Pathogenic/Likely pathogenic ★★ same condition
COL4A4 c.(1029+1_1030-1 Pathogenic ★ same condition
COL4A4 p.Ala399fs Likely pathogenic ★ same condition
COL4A4 p.Gly722fs Pathogenic ★ same condition
COL4A4 p.Lys1324fs Pathogenic ★ same condition
COL4A4 p.Arg877_Gly885dup Conflicting classifications of pathogenicity ★ same condition
COL4A4 p.Pro228Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
COL4A4 p.Pro228= Likely benign ★ same residue

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-pro228fs (accessed [today's date]).

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