Is COL4A5 p.Arg249Ter (c.745A>T) pathogenic?

COL4A5 p.Arg249Ter (c.745A>T) is classified Likely pathogenic in COL4A5 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-06). Absent from gnomAD v4.1; Associated with X-linked Alport syndrome.

What condition is associated with COL4A5 p.Arg249Ter (c.745A>T)?

COL4A5 p.Arg249Ter (c.745A>T) is associated with X-linked Alport syndrome (ClinVar).

How common is COL4A5 p.Arg249Ter (c.745A>T) in the general population?

COL4A5 p.Arg249Ter (c.745A>T) is absent from gnomAD v4.1 (gnomAD).

How is Alport syndrome inherited?

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

COL4A5 p.Arg249Ter

c.745A>T · rs2066188778 · VCV983611

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

X-linked Alport syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 13 of 53
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.1, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COL4A5
Protein: p.Arg249Ter
Coding: c.745A>T
MANE Select: NM_033380
dbSNP: rs2066188778
Type: single nucleotide variant
Location: chrX:108578348 (GRCh38)
Structure: AlphaFold pLDDT 49.04 · 2 PDB
Residue 249: 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 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
COL4A5 c.1780-1G>T Pathogenic ★★ same condition
COL4A5 c.2042-2A>G 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/col4a5-p-arg249ter (accessed [today's date]).

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