Is COL4A5 p.Pro1320Ser (c.3958C>T) pathogenic?

COL4A5 p.Pro1320Ser (c.3958C>T) is classified Conflicting classifications of pathogenicity in COL4A5 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1284); Rare (popmax 0.409%, eas); Associated with X-linked Alport syndrome.

What condition is associated with COL4A5 p.Pro1320Ser (c.3958C>T)?

COL4A5 p.Pro1320Ser (c.3958C>T) is associated with X-linked Alport syndrome (ClinVar).

How common is COL4A5 p.Pro1320Ser (c.3958C>T) in the general population?

COL4A5 p.Pro1320Ser (c.3958C>T) is rare (popmax 0.409%, eas) (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.Pro1320Ser (c.3958C>T)?

AlphaMissense predicts likely benign (score 0.1284) — an in-silico prediction, not a clinical call.

COL4A5 p.Pro1320Ser

c.3958C>T · rs754836509 · VCV447208

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1284 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.409%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked Alport syndrome

Computational evidence

Protein change
AlphaMissense	0.1284	likely benign
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -9.68	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 5.8	GERP 2.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 256 kb · p 6e-09 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1314S vs ClinVar P1320S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.409% East Asian · 138/33,705 alleles

Filtering AF 0.354% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.333%

Overall 0.0129% 156/1,207,663 alleles · rare exomes 139/1,096,632 · genomes 17/111,031 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.409%	244
Remaining individualsnot grpmax-eligible	0.00842%	11,881
South Asian	0.00529%	18,904
Finnishnot grpmax-eligible	0.00215%	46,437
European (non-Finnish)	0.00112%	89,381

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.Pro1320Ser
Coding: c.3958C>T
MANE Select: NM_033380
dbSNP: rs754836509
Type: single nucleotide variant
Location: chrX:108680694 (GRCh38)
Structure: AlphaFold pLDDT 49.04 · 2 PDB
Residue 1314 UniProt numbering: 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.Pro1320Leu Uncertain significance ★★ ⚠ same residue
COL4A5 p.Pro1320= Benign/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-pro1320ser (accessed [today's date]).

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