Is COL4A3 p.Pro705= (c.2115T>A) pathogenic?

COL4A3 p.Pro705= (c.2115T>A) is classified Conflicting classifications of pathogenicity in COL4A3 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-03-01). Ultra-rare (popmax 0.0496%, mid); Associated with autosomal recessive Alport syndrome.

What condition is associated with COL4A3 p.Pro705= (c.2115T>A)?

COL4A3 p.Pro705= (c.2115T>A) is associated with autosomal recessive Alport syndrome, autosomal dominant Alport syndrome, hematuria, benign familial (ClinVar).

How common is COL4A3 p.Pro705= (c.2115T>A) in the general population?

COL4A3 p.Pro705= (c.2115T>A) is ultra-rare (popmax 0.0496%, mid) (gnomAD).

How is Alport syndrome inherited?

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

COL4A3 p.Pro705=

c.2115T>A · rs201419174 · VCV369945

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, mid)

Conditions

autosomal recessive 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 0.27	GERP -2.4, phastCons 0.99
Overall
CADD	8.275	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0496% Middle Eastern · 3/6,046 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0072%

Overall 0.00386% 62/1,607,042 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0496%	2,015
Admixed American	0.0118%	8,499
Remaining individualsnot grpmax-eligible	0.00481%	20,776
European (non-Finnish)	0.00417%	23,993

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: COL4A3
Protein: p.Pro705=
Coding: c.2115T>A
MANE Select: NM_000091
dbSNP: rs201419174
Type: single nucleotide variant
Location: chr2:227277543 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 48.64 · 2 PDB
Residue 705: the 'triple-helical region' region; the 'disordered' region

Full COL4A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: autosomal dominant Alport syndrome hematuria, benign familial

For Alport syndrome (Orphanet):

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

Similar variants

COL4A3 c.1114+1G>A Likely pathogenic ★★ same condition
COL4A3 c.1114+2T>C Pathogenic/Likely pathogenic ★★ same condition
COL4A3 c.1408+1G>C Pathogenic/Likely pathogenic ★★ same condition
COL4A3 c.1504+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A3 c.2489-1G>A Likely pathogenic ★★ same condition
COL4A3 c.2656+1G>T Pathogenic/Likely pathogenic ★★ same condition
COL4A3 c.2746+1G>T Pathogenic ★★ same condition
COL4A3 c.2747-1G>C 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/col4a3-p-pro705 (accessed [today's date]).

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