Is COL4A4 p.Pro334fs (c.999dup) pathogenic?

COL4A4 p.Pro334fs (c.999dup) is classified Pathogenic in COL4A4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-05). Very rare (popmax 0.0011%, sas).

How common is COL4A4 p.Pro334fs (c.999dup) in the general population?

COL4A4 p.Pro334fs (c.999dup) is very rare (popmax 0.0011%, sas) (gnomAD).

COL4A4 p.Pro334fs

c.999dup · rs760803010 · VCV1453686

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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 17 of 48
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.6	GERP 1.8, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,804 alleles

Overall 6.85e-05% 1/1,460,450 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: COL4A4
Protein: p.Pro334fs
Coding: c.999dup
MANE Select: NM_000092
dbSNP: rs760803010
Type: Duplication
Location: chr2:227101533 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 334: the 'triple-helical region' region

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

Similar variants

COL4A4 p.Pro334His Uncertain significance ★ ⚠ same residue
COL4A4 p.Ala1546fs Pathogenic/Likely pathogenic ★★ same type
COL4A4 p.Arg1114fs Pathogenic/Likely pathogenic ★★ same type
COL4A4 p.Cys1588fs Pathogenic/Likely pathogenic ★★ same type
COL4A4 p.Gln1105fs Pathogenic/Likely pathogenic ★★ same type
COL4A4 p.Gly226fs Pathogenic/Likely pathogenic ★★ same type
COL4A4 p.Gly388fs Pathogenic ★★ same type
COL4A4 p.Gly503fs 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/col4a4-p-pro334fs (accessed [today's date]).

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