Is COL4A4 p.Pro1366= (c.4098G>A) pathogenic?

COL4A4 p.Pro1366= (c.4098G>A) is classified Likely benign in COL4A4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-06-01). Very rare (popmax 0.00667%, amr); Associated with hematuria, benign familial.

What condition is associated with COL4A4 p.Pro1366= (c.4098G>A)?

COL4A4 p.Pro1366= (c.4098G>A) is associated with hematuria, benign familial, autosomal recessive Alport syndrome (ClinVar).

How common is COL4A4 p.Pro1366= (c.4098G>A) in the general population?

COL4A4 p.Pro1366= (c.4098G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

COL4A4 p.Pro1366=

c.4098G>A · rs772611085 · VCV514048

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

hematuria, benign familial

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.6	GERP -3.5
Overall
CADD	1.395	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,998 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00149% 24/1,613,954 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,999
South Asian	0.00329%	30,361
Remaining individualsnot grpmax-eligible	0.0032%	31,245
East Asian	0.00223%	44,886
European (non-Finnish)	0.00119%	84,287

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.Pro1366=
Coding: c.4098G>A
MANE Select: NM_000092
dbSNP: rs772611085
Type: single nucleotide variant
Location: chr2:227022166 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 1366: the 'triple-helical region' region; the 'disordered' region

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

Disease context

hematuria, benign familial — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive Alport syndrome

Similar variants

COL4A4 p.Pro1366Ser Uncertain significance ★★ ⚠ same residue
COL4A4 p.Pro1366Leu 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

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-pro1366 (accessed [today's date]).

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