Is COL4A4 p.Pro730Leu (c.2189C>T) pathogenic?

COL4A4 p.Pro730Leu (c.2189C>T) is classified Uncertain significance in COL4A4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-11). AlphaMissense: likely benign (0.081); Ultra-rare (popmax 0.0133%, amr); Associated with autosomal recessive Alport syndrome.

What condition is associated with COL4A4 p.Pro730Leu (c.2189C>T)?

COL4A4 p.Pro730Leu (c.2189C>T) is associated with autosomal recessive Alport syndrome, hematuria, benign familial, 1 (ClinVar).

How common is COL4A4 p.Pro730Leu (c.2189C>T) in the general population?

COL4A4 p.Pro730Leu (c.2189C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

How is Alport syndrome inherited?

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

What do computational predictors say about COL4A4 p.Pro730Leu (c.2189C>T)?

AlphaMissense predicts likely benign (score 0.081) — an in-silico prediction, not a clinical call.

COL4A4 p.Pro730Leu

c.2189C>T · rs747641722 · VCV2146013

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.081 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive Alport syndrome

Computational evidence

Protein change
AlphaMissense	0.081	likely benign
REVEL	0.679	pathogenic-leaning
SaProt	LLR -9.29	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 140 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/59,988 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00149% 24/1,613,784 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,499
East Asian	0.00669%	14,959
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.000932%	107,270

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.Pro730Leu
Coding: c.2189C>T
MANE Select: NM_000092
dbSNP: rs747641722
Type: single nucleotide variant
Location: chr2:227059599 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 730: the 'triple-helical region' region; the 'disordered' region

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

Disease context

autosomal recessive Alport syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hematuria, benign familial, 1

For Alport syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked dominant
Onset: Adolescent, Adult, Childhood, Elderly

Similar variants

COL4A4 p.Pro730= Conflicting classifications of pathogenicity ★ 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-pro730leu (accessed [today's date]).

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