Is COL4A4 p.Pro1587Arg (c.4760C>G) pathogenic?

COL4A4 p.Pro1587Arg (c.4760C>G) is classified Conflicting classifications of pathogenicity in COL4A4 (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0806); Rare (popmax 0.424%, nfe); Associated with Alport syndrome.

What condition is associated with COL4A4 p.Pro1587Arg (c.4760C>G)?

COL4A4 p.Pro1587Arg (c.4760C>G) is associated with Alport syndrome (ClinVar).

How common is COL4A4 p.Pro1587Arg (c.4760C>G) in the general population?

COL4A4 p.Pro1587Arg (c.4760C>G) is rare (popmax 0.424%, nfe) (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.Pro1587Arg (c.4760C>G)?

AlphaMissense predicts likely benign (score 0.0806) — an in-silico prediction, not a clinical call.

COL4A4 p.Pro1587Arg

c.4760C>G · rs190148408 · VCV447189

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.0806 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.424%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Alport syndrome

Computational evidence

Protein change
AlphaMissense	0.0806	likely benign
REVEL	0.327	indeterminate
SaProt	LLR -6.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP -0.085, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 140 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	16.8	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 0.424% European (non-Finnish) · 5,000/1,180,000 alleles

Filtering AF 0.414% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.41%

Overall 0.342% 5,525/1,613,882 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.424%	236
Remaining individualsnot grpmax-eligible	0.317%	316
Ashkenazi Jewishnot grpmax-eligible	0.196%	510
South Asian	0.153%	655
Middle Eastern	0.0825%	1,212
Admixed American	0.0733%	1,364
African / African-American	0.0693%	1,443
Finnishnot grpmax-eligible	0.0392%	2,549
East Asian	0.00891%	11,222

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.Pro1587Arg
Coding: c.4760C>G
MANE Select: NM_000092
dbSNP: rs190148408
Type: single nucleotide variant
Location: chr2:227008067 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 1587: the collagen iv nc1 domain; an α-helix

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

Disease context

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

COL4A4 p.Pro1587Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
COL4A4 p.Pro1587= Uncertain significance same residue
COL4A4 p.Pro1587Ala Uncertain significance ★★ ⚠ same residue
COL4A4 p.Pro1587Gln Likely benign ★ same residue
COL4A4 c.1030-2A>C Likely pathogenic ★★ same condition
COL4A4 c.1369+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A4 c.1370-2A>C Likely pathogenic ★★ same condition
COL4A4 c.1696+1G>A 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-pro1587arg (accessed [today's date]).

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