Is COL4A4 p.Pro66= (c.198A>G) pathogenic?

COL4A4 p.Pro66= (c.198A>G) is classified Benign/Likely benign in COL4A4 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-31). Low-frequency (popmax 2.22%, afr); Associated with kidney disorder.

What condition is associated with COL4A4 p.Pro66= (c.198A>G)?

COL4A4 p.Pro66= (c.198A>G) is associated with kidney disorder, Alport syndrome (ClinVar).

How common is COL4A4 p.Pro66= (c.198A>G) in the general population?

COL4A4 p.Pro66= (c.198A>G) is low-frequency (popmax 2.22%, afr) (gnomAD).

COL4A4 p.Pro66=

c.198A>G · rs147947155 · VCV447182

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.22%, afr)

Conditions

kidney disorder

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 -4.4	GERP -4.7
Overall
CADD	0.929	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.22% African / African-American · 1,664/75,008 alleles

Filtering AF 2.13% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.09%

Overall 0.121% 1,958/1,613,988 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.22%	45
Middle Eastern	0.33%	303
Remaining individualsnot grpmax-eligible	0.218%	460
Admixed American	0.123%	811
South Asian	0.011%	9,107
European (non-Finnish)	0.00458%	21,851

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.Pro66=
Coding: c.198A>G
MANE Select: NM_000092
dbSNP: rs147947155
Type: single nucleotide variant
Location: chr2:227121143 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 66: the 'disordered' region; the 'triple-helical region' region

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

Disease context

kidney disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Alport syndrome

Similar variants

COL4A4 p.Pro66Ser Conflicting classifications of pathogenicity ★ ⚠ 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
COL4A4 c.1696+1G>T Likely pathogenic ★★ same condition
COL4A4 c.1697-1G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A4 c.1803+2T>C 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-pro66 (accessed [today's date]).

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