Is COL4A3 p.Pro77fs (c.226_229dup) pathogenic?

COL4A3 p.Pro77fs (c.226229dup) is classified Pathogenic in COL4A3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-14). Very rare (popmax 0.00267%, afr).

How common is COL4A3 p.Pro77fs (c.226_229dup) in the general population?

COL4A3 p.Pro77fs (c.226_229dup) is very rare (popmax 0.00267%, afr) (gnomAD).

COL4A3 p.Pro77fs

c.226_229dup · rs950553574 · VCV2807395

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

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 3 of 52
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.9	GERP -3.5, phastCons 1
Overall
CADD	32.0	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 0.00267% African / African-American · 2/74,854 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,609,650 alleles · very rare exomes 1/1,457,498 · genomes 1/152,152 · 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: COL4A3
Protein: p.Pro77fs
Coding: c.226_229dup
MANE Select: NM_000091
dbSNP: rs950553574
Type: Duplication
Location: chr2:227240223 (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 77: the 'triple-helical region' region; the 'disordered' region

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

Similar variants

COL4A3 c.1575+2dup Likely pathogenic ★★ same type
COL4A3 c.3883-2067_4311dup Pathogenic/Likely pathogenic ★★ same type
COL4A3 p.Glu260fs Pathogenic ★★ same type
COL4A3 p.Glu647fs Pathogenic/Likely pathogenic ★★ same type
COL4A3 p.Gly1183dup Pathogenic/Likely pathogenic ★★ same type
COL4A3 p.Gly807fs Pathogenic/Likely pathogenic ★★ same type
COL4A3 p.Leu558fs Pathogenic ★★ same type
COL4A3 p.Met726fs Pathogenic/Likely pathogenic ★★ same type

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-pro77fs (accessed [today's date]).

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