Is COL4A4 p.Arg349Ter (c.1045C>T) pathogenic?

COL4A4 p.Arg349Ter (c.1045C>T) is classified Pathogenic/Likely pathogenic in COL4A4 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-04-17). Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with COL4A4 p.Arg349Ter (c.1045C>T)?

COL4A4 p.Arg349Ter (c.1045C>T) is associated with Inborn genetic diseases, nephrotic syndrome, autosomal dominant Alport syndrome (ClinVar).

How common is COL4A4 p.Arg349Ter (c.1045C>T) in the general population?

COL4A4 p.Arg349Ter (c.1045C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

COL4A4 p.Arg349Ter

c.1045C>T · rs534522842 · VCV447178

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 18 of 48
Splicing
SpliceAI	Δ0.34	acceptor loss · deltas
Pangolin	Δ0.22	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Overall
CADD	41.0	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 0.00333% Admixed American · 2/60,020 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00131% 2/152,290 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.Arg349Ter
Coding: c.1045C>T
MANE Select: NM_000092
dbSNP: rs534522842
Type: single nucleotide variant
Location: chr2:227099674 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 349: the 'triple-helical region' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephrotic syndrome autosomal dominant Alport syndrome hematuria, benign familial, 1 autosomal recessive Alport syndrome

Similar variants

COL4A4 p.Arg349Gln Likely benign ★ same residue
COL4A4 c.1030-2A>C Likely pathogenic ★★ same condition
COL4A4 c.1099+1G>T Pathogenic/Likely pathogenic ★★ same condition
COL4A4 c.1369+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A4 c.1459+1G>A Pathogenic ★★ same condition
COL4A4 c.1696+1G>A Likely pathogenic ★★ same condition
COL4A4 c.1696+1G>T Likely pathogenic ★★ same condition
COL4A4 c.1697-1G>A Pathogenic/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-arg349ter (accessed [today's date]).

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