Is COL4A4 p.Lys1228= (c.3684G>A) pathogenic?

COL4A4 p.Lys1228= (c.3684G>A) is classified Benign in COL4A4 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). Common (popmax 56.9%, sas) — too common for a highly-penetrant pathogenic allele; Associated with Alport syndrome.

What condition is associated with COL4A4 p.Lys1228= (c.3684G>A)?

COL4A4 p.Lys1228= (c.3684G>A) is associated with Alport syndrome, autosomal recessive Alport syndrome (ClinVar).

How is Alport syndrome inherited?

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

COL4A4 p.Lys1228=

Q: How common is COL4A4 p.Lys1228= (c.3684G>A) in the general population?

COL4A4 p.Lys1228= (c.3684G>A) is common (popmax 56.9%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3684G>A · rs2229812 · VCV255032

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Common

common (popmax 56.9%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

Alport syndrome

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 0.068	GERP -3.3, phastCons 0.97
Overall
CADD	0.368	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 56.9% South Asian · 51,827/91,066 alleles

Filtering AF 56.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 56.3%

Overall 44.4% 716,844/1,613,548 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	56.9%	2
African / African-American	53%	2
Ashkenazi Jewishnot grpmax-eligible	51.9%	2
Admixed American	51.3%	2
Finnishnot grpmax-eligible	49.8%	2
Remaining individualsnot grpmax-eligible	44.5%	2
European (non-Finnish)	42.3%	2
Amishnot grpmax-eligible	40.4%	2
East Asian	40.2%	2
Middle Eastern	39.8%	3

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.Lys1228=
Coding: c.3684G>A
MANE Select: NM_000092
dbSNP: rs2229812
Type: single nucleotide variant
Location: chr2:227032170 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 1228: the 'triple-helical region' region; the 'disordered' region

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

Also linked: autosomal recessive Alport syndrome

For Alport syndrome (Orphanet):

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

Similar variants

COL4A4 p.Lys1228Arg 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
COL4A4 c.1696+1G>T 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-lys1228 (accessed [today's date]).

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