Is COL4A5 p.Pro1335Ser (c.4003C>T) pathogenic?

COL4A5 p.Pro1335Ser (c.4003C>T) is classified Conflicting classifications of pathogenicity in COL4A5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-03-14). AlphaMissense: likely benign (0.1146); Ultra-rare (popmax 0.0682%, eas).

How common is COL4A5 p.Pro1335Ser (c.4003C>T) in the general population?

COL4A5 p.Pro1335Ser (c.4003C>T) is ultra-rare (popmax 0.0682%, eas) (gnomAD).

What do computational predictors say about COL4A5 p.Pro1335Ser (c.4003C>T)?

AlphaMissense predicts likely benign (score 0.1146) — an in-silico prediction, not a clinical call.

COL4A5 p.Pro1335Ser

c.4003C>T · rs757653472 · VCV1164399

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1146 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0682%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1146	likely benign
REVEL	0.746	pathogenic-leaning
SaProt	LLR -9.98	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 1.8, 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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1329S vs ClinVar P1335S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0682% East Asian · 23/33,725 alleles

Filtering AF 0.0466% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0395%

Overall 0.00224% 27/1,207,240 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0682%	1,466
South Asian	0.00353%	28,356
European (non-Finnish)	0.000224%	446,634

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.Pro1335Ser
Coding: c.4003C>T
MANE Select: NM_033380
dbSNP: rs757653472
Type: single nucleotide variant
Location: chrX:108680739 (GRCh38)
Structure: AlphaFold pLDDT 49.04 · 2 PDB
Residue 1335: the 'triple-helical region' region; the 'disordered' region

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

Similar variants

COL4A5 p.Pro1335fs Pathogenic ★ same residue
COL4A5 c.1032+1G>C Pathogenic/Likely pathogenic ★★ same type
COL4A5 c.1033-1G>A Pathogenic ★★ same type
COL4A5 c.1033-2A>G Pathogenic/Likely pathogenic ★★ same type
COL4A5 c.1339+1G>A Pathogenic/Likely pathogenic ★★ same type
COL4A5 c.141+1G>A Pathogenic ★★ same type
COL4A5 c.1423+1G>A Pathogenic ★★ same type
COL4A5 c.1424-20T>A Pathogenic/Likely pathogenic ★★ same type

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-pro1335ser (accessed [today's date]).

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