Is COL4A4 p.Arg64= (c.192G>A) pathogenic?

COL4A4 p.Arg64= (c.192G>A) is classified Conflicting classifications of pathogenicity in COL4A4 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-06-03). Very rare (popmax 0.00314%, nfe); Associated with autosomal dominant Alport syndrome.

What condition is associated with COL4A4 p.Arg64= (c.192G>A)?

COL4A4 p.Arg64= (c.192G>A) is associated with autosomal dominant Alport syndrome, hematuria, benign familial, 1, autosomal recessive Alport syndrome (ClinVar).

How common is COL4A4 p.Arg64= (c.192G>A) in the general population?

COL4A4 p.Arg64= (c.192G>A) is very rare (popmax 0.00314%, nfe) (gnomAD).

How is Alport syndrome inherited?

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

COL4A4 p.Arg64=

c.192G>A · rs748152418 · VCV999493

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Conditions

autosomal dominant Alport syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.50	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.30	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 2.6, phastCons 1
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00314% European (non-Finnish) · 37/1,179,428 alleles

Filtering AF 0.00232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00242% 39/1,613,284 alleles · very rare exomes 37/1,461,194 · genomes 2/152,090 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00314%	31,876
African / African-American	0.00267%	37,426

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.Arg64=
Coding: c.192G>A
MANE Select: NM_000092
dbSNP: rs748152418
Type: single nucleotide variant
Location: chr2:227140161 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 64: the '7s domain' region; the 'disordered' region

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

Disease context

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

Also linked: hematuria, benign familial, 1 autosomal recessive Alport syndrome Alport syndrome

For Alport syndrome (Orphanet):

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

Similar variants

COL4A4 p.Arg64Gln Uncertain significance ★★ ⚠ same residue
COL4A4 p.Arg64Trp 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-arg64 (accessed [today's date]).

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