Is COL4A5 p.Pro668Leu (c.2003C>T) pathogenic?

COL4A5 p.Pro668Leu (c.2003C>T) is classified Uncertain significance in COL4A5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-28). AlphaMissense: likely benign (0.0744); Very rare (popmax 0.000895%, nfe); Associated with X-linked Alport syndrome.

What condition is associated with COL4A5 p.Pro668Leu (c.2003C>T)?

COL4A5 p.Pro668Leu (c.2003C>T) is associated with X-linked Alport syndrome (ClinVar).

How common is COL4A5 p.Pro668Leu (c.2003C>T) in the general population?

COL4A5 p.Pro668Leu (c.2003C>T) is very rare (popmax 0.000895%, nfe) (gnomAD).

How is Alport syndrome inherited?

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

What do computational predictors say about COL4A5 p.Pro668Leu (c.2003C>T)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

COL4A5 p.Pro668Leu

c.2003C>T · rs1569494888 · VCV1807134

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000895%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked Alport syndrome

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.742	pathogenic-leaning
SaProt	LLR -13.52	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 256 kb · p 6e-09 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000895% European (non-Finnish) · 8/893,897 alleles

Filtering AF 0.000385% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000278%

Overall 0.000731% 8/1,095,036 alleles · very rare

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: COL4A5
Protein: p.Pro668Leu
Coding: c.2003C>T
MANE Select: NM_033380
dbSNP: rs1569494888
Type: single nucleotide variant
Location: chrX:108601447 (GRCh38)
Structure: AlphaFold pLDDT 49.04 · 2 PDB
Residue 668: the 'triple-helical region' region; the 'disordered' region

Full COL4A5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

X-linked 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

COL4A5 p.Pro668Ser Uncertain significance ★ ⚠ same residue
COL4A5 p.Pro668= Likely benign ★ same residue
COL4A5 c.1033-1G>A Pathogenic ★★ same condition
COL4A5 c.1033-2A>G Pathogenic/Likely pathogenic ★★ same condition
COL4A5 c.1339+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A5 c.141+1G>A Pathogenic ★★ same condition
COL4A5 c.1424-20T>A Pathogenic/Likely pathogenic ★★ same condition
COL4A5 c.1516+1G>C 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/col4a5-p-pro668leu (accessed [today's date]).

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