Is COL4A5 p.Pro1576Ala (c.4726C>G) pathogenic?

COL4A5 p.Pro1576Ala (c.4726C>G) is classified Uncertain significance in COL4A5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-12). AlphaMissense: likely benign (0.1678); Very rare (popmax 0.00219%, amr); Associated with X-linked Alport syndrome.

What condition is associated with COL4A5 p.Pro1576Ala (c.4726C>G)?

COL4A5 p.Pro1576Ala (c.4726C>G) is associated with X-linked Alport syndrome (ClinVar).

How common is COL4A5 p.Pro1576Ala (c.4726C>G) in the general population?

COL4A5 p.Pro1576Ala (c.4726C>G) is very rare (popmax 0.00219%, 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 COL4A5 p.Pro1576Ala (c.4726C>G)?

AlphaMissense predicts likely benign (score 0.1678) — an in-silico prediction, not a clinical call.

COL4A5 p.Pro1576Ala

c.4726C>G · rs747041833 · VCV585547

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1678 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00219%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked Alport syndrome

Computational evidence

Protein change
AlphaMissense	0.1678	likely benign
REVEL	0.807	moderately pathogenic-leaning
SaProt	LLR -11.77	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 256 kb · p 6e-09 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1570A vs ClinVar P1576A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00219% Admixed American · 1/45,679 alleles

Overall 0.000249% 3/1,206,466 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00219%	45,679
Remaining individualsnot grpmax-eligible	0.00211%	47,491
European (non-Finnish)	0.000112%	892,323

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: COL4A5
Protein: p.Pro1576Ala
Coding: c.4726C>G
MANE Select: NM_033380
dbSNP: rs747041833
Type: single nucleotide variant
Location: chrX:108694826 (GRCh38)
Structure: AlphaFold pLDDT 49.04 · 2 PDB
Residue 1576: the collagen iv nc1 domain; a β-strand

Full COL4A5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

X-linked Alport syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Alport syndrome (Orphanet):

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

Similar variants

COL4A5 p.Pro1576Ser Likely benign ★ ⚠ same residue
COL4A5 c.1033-1G>A Pathogenic ★★ same condition
COL4A5 c.1033-2A>G Pathogenic/Likely pathogenic ★★ same condition
COL4A5 c.1339+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A5 c.141+1G>A Pathogenic ★★ same condition
COL4A5 c.1424-20T>A Pathogenic/Likely pathogenic ★★ same condition
COL4A5 c.1516+1G>C Pathogenic ★★ same condition
COL4A5 c.1780-1G>T 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/col4a5-p-pro1576ala (accessed [today's date]).

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