Is COL4A3 p.Pro616fs (c.1845dup) pathogenic?

COL4A3 p.Pro616fs (c.1845dup) is classified Pathogenic/Likely pathogenic in COL4A3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-27). Very rare (popmax 0.00833%, amr); Associated with Alport syndrome.

What condition is associated with COL4A3 p.Pro616fs (c.1845dup)?

COL4A3 p.Pro616fs (c.1845dup) is associated with Alport syndrome (ClinVar).

How common is COL4A3 p.Pro616fs (c.1845dup) in the general population?

COL4A3 p.Pro616fs (c.1845dup) is very rare (popmax 0.00833%, amr) (gnomAD).

How is Alport syndrome inherited?

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

COL4A3 p.Pro616fs

c.1845dup · rs1478523884 · VCV2734418

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Conditions

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 26 of 52
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.6	GERP 0.94, phastCons 0.65
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/59,996 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00031% 5/1,613,990 alleles · very rare

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: COL4A3
Protein: p.Pro616fs
Coding: c.1845dup
MANE Select: NM_000091
dbSNP: rs1478523884
Type: Duplication
Location: chr2:227273034 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 48.64 · 2 PDB
Residue 616: the 'triple-helical region' region; the 'disordered' region

Full COL4A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

COL4A3 p.Glu647fs Pathogenic/Likely pathogenic ★★ same condition
COL4A3 p.Gly1183dup Pathogenic/Likely pathogenic ★★ same condition
COL4A3 p.Gly807fs Pathogenic/Likely pathogenic ★★ same condition
COL4A3 p.Met726fs Pathogenic/Likely pathogenic ★★ same condition
COL4A3 c.830dup Likely pathogenic ★ same condition
COL4A3 p.Asp1566Ter Likely pathogenic ★ same condition
COL4A3 p.Tyr1625fs Likely pathogenic ★ same condition
COL4A3 p.Gly780_Thr781insLeuProGlyLeuProGly 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/col4a3-p-pro616fs (accessed [today's date]).

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