Is COL4A5 p.Pro816Ser (c.2446C>T) pathogenic?

COL4A5 p.Pro816Ser (c.2446C>T) is classified Conflicting classifications of pathogenicity in COL4A5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-09-28). AlphaMissense: likely benign (0.1162); Absent from gnomAD v4.1; Associated with X-linked Alport syndrome.

What condition is associated with COL4A5 p.Pro816Ser (c.2446C>T)?

COL4A5 p.Pro816Ser (c.2446C>T) is associated with X-linked Alport syndrome (ClinVar).

How common is COL4A5 p.Pro816Ser (c.2446C>T) in the general population?

COL4A5 p.Pro816Ser (c.2446C>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.

What do computational predictors say about COL4A5 p.Pro816Ser (c.2446C>T)?

AlphaMissense predicts likely benign (score 0.1162) — an in-silico prediction, not a clinical call.

COL4A5 p.Pro816Ser

c.2446C>T · rs2524375503 · VCV3068399

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1162 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked Alport syndrome

Computational evidence

Protein change
AlphaMissense	0.1162	likely benign
REVEL	0.774	moderately pathogenic-leaning
SaProt	LLR -9.82	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 256 kb · p 6e-09 · regional, not allelic
Overall
CADD	23.5	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

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.Pro816Ser
Coding: c.2446C>T
MANE Select: NM_033380
dbSNP: rs2524375503
Type: single nucleotide variant
Location: chrX:108614961 (GRCh38)
Structure: AlphaFold pLDDT 49.04 · 2 PDB
Residue 816: 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-pro816ser (accessed [today's date]).

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