Is COL4A4 p.Ala555= (c.1665G>A) pathogenic?

COL4A4 p.Ala555= (c.1665G>A) is classified Likely benign in COL4A4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.033%, mid); Associated with hematuria, benign familial.

What condition is associated with COL4A4 p.Ala555= (c.1665G>A)?

COL4A4 p.Ala555= (c.1665G>A) is associated with hematuria, benign familial, autosomal recessive Alport syndrome, Alport syndrome (ClinVar).

How common is COL4A4 p.Ala555= (c.1665G>A) in the general population?

COL4A4 p.Ala555= (c.1665G>A) is ultra-rare (popmax 0.033%, mid) (gnomAD).

COL4A4 p.Ala555=

c.1665G>A · rs137880920 · VCV722931

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

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 -0.071	GERP -3.3, phastCons 0.88
Overall
CADD	6.069	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.00483% 78/1,614,160 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
African / African-American	0.0133%	7,504
South Asian	0.0121%	8,281
Admixed American	0.01%	10,004
Remaining individualsnot grpmax-eligible	0.0048%	20,837
East Asian	0.00446%	22,436
European (non-Finnish)	0.00373%	26,818

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.Ala555=
Coding: c.1665G>A
MANE Select: NM_000092
dbSNP: rs137880920
Type: single nucleotide variant
Location: chr2:227082146 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 555: 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 Alport syndrome

Similar variants

COL4A4 p.Ala555Val Conflicting classifications of pathogenicity ★ ⚠ same residue
COL4A4 p.Ala555Gly Uncertain significance ★ ⚠ 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.1370-2A>C Likely pathogenic ★★ same condition
COL4A4 c.1459+1G>A 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-ala555 (accessed [today's date]).

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