Is COL4A4 p.His5= (c.15C>T) pathogenic?

COL4A4 p.His5= (c.15C>T) is classified Conflicting classifications of pathogenicity in COL4A4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-26). Ultra-rare (popmax 0.0242%, nfe); Associated with Alport syndrome.

What condition is associated with COL4A4 p.His5= (c.15C>T)?

COL4A4 p.His5= (c.15C>T) is associated with Alport syndrome (ClinVar).

How common is COL4A4 p.His5= (c.15C>T) in the general population?

COL4A4 p.His5= (c.15C>T) is ultra-rare (popmax 0.0242%, 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.His5=

c.15C>T · rs199504524 · VCV895855

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, nfe)

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 2	GERP 0.74, phastCons 0.014
Overall
CADD	1.954	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0242% European (non-Finnish) · 286/1,179,748 alleles

Filtering AF 0.0219% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.0187% 302/1,613,712 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0242%	4,125
Remaining individualsnot grpmax-eligible	0.0144%	6,942
African / African-American	0.00933%	10,714

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.His5=
Coding: c.15C>T
MANE Select: NM_000092
dbSNP: rs199504524
Type: single nucleotide variant
Location: chr2:227147469 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB

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-his5 (accessed [today's date]).

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