Is COL4A4 p.Pro1619= (c.4857T>C) pathogenic?

COL4A4 p.Pro1619= (c.4857T>C) is classified Benign/Likely benign in COL4A4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-28). Rare (popmax 0.669%, eas); Associated with Alport syndrome.

What condition is associated with COL4A4 p.Pro1619= (c.4857T>C)?

COL4A4 p.Pro1619= (c.4857T>C) is associated with Alport syndrome (ClinVar).

How common is COL4A4 p.Pro1619= (c.4857T>C) in the general population?

COL4A4 p.Pro1619= (c.4857T>C) is rare (popmax 0.669%, eas) (gnomAD).

How is Alport syndrome inherited?

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

COL4A4 p.Pro1619=

c.4857T>C · rs184776061 · VCV334700

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.669%, eas)

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 -8	GERP -3.9
Overall
CADD	0.105	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.669% East Asian · 300/44,874 alleles

Filtering AF 0.606% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.582%

Overall 0.0205% 331/1,613,284 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.669%	150
Ashkenazi Jewishnot grpmax-eligible	0.0439%	2,277
Remaining individualsnot grpmax-eligible	0.016%	6,240
South Asian	0.00549%	18,209
Admixed American	0.00167%	60,020
European (non-Finnish)	0.000169%	590,012

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.Pro1619=
Coding: c.4857T>C
MANE Select: NM_000092
dbSNP: rs184776061
Type: single nucleotide variant
Location: chr2:227007541 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 1619: the collagen iv nc1 domain; a disulfide bond; 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 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
COL4A4 c.2383+1G>A 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-pro1619 (accessed [today's date]).

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