Is COL4A5 p.Gly276Ser (c.826G>A) pathogenic?

COL4A5 p.Gly276Ser (c.826G>A) is classified Likely pathogenic in COL4A5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-06). AlphaMissense: ambiguous (0.5461); Very rare (popmax 0.00176%, sas); Associated with X-linked Alport syndrome.

What condition is associated with COL4A5 p.Gly276Ser (c.826G>A)?

COL4A5 p.Gly276Ser (c.826G>A) is associated with X-linked Alport syndrome (ClinVar).

How common is COL4A5 p.Gly276Ser (c.826G>A) in the general population?

COL4A5 p.Gly276Ser (c.826G>A) is very rare (popmax 0.00176%, sas) (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.Gly276Ser (c.826G>A)?

AlphaMissense predicts ambiguous (score 0.5461) — an in-silico prediction, not a clinical call.

COL4A5 p.Gly276Ser

c.826G>A · rs1314371806 · VCV1993856

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5461 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

X-linked Alport syndrome

Computational evidence

Protein change
AlphaMissense	0.5461	ambiguous
REVEL	0.908	moderately pathogenic-leaning
SaProt	LLR -13.04	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 256 kb · p 6e-09 · regional, not allelic
Overall
CADD	25.8	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 0.00176% South Asian · 1/56,917 alleles

Overall 9.13e-05% 1/1,095,362 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.Gly276Ser
Coding: c.826G>A
MANE Select: NM_033380
dbSNP: rs1314371806
Type: single nucleotide variant
Location: chrX:108580578 (GRCh38)
Structure: AlphaFold pLDDT 49.04 · 2 PDB
Residue 276: 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.Gly276Val Likely pathogenic ★ 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
COL4A5 c.1780-1G>T 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-gly276ser (accessed [today's date]).

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