Is COL4A3 p.Pro1109Ser (c.3325C>T) pathogenic?

COL4A3 p.Pro1109Ser (c.3325C>T) is classified Conflicting classifications of pathogenicity in COL4A3 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.0793); Rare (popmax 0.694%, nfe); Associated with kidney disorder.

What condition is associated with COL4A3 p.Pro1109Ser (c.3325C>T)?

COL4A3 p.Pro1109Ser (c.3325C>T) is associated with kidney disorder, Alport syndrome (ClinVar).

How common is COL4A3 p.Pro1109Ser (c.3325C>T) in the general population?

COL4A3 p.Pro1109Ser (c.3325C>T) is rare (popmax 0.694%, nfe) (gnomAD).

What do computational predictors say about COL4A3 p.Pro1109Ser (c.3325C>T)?

AlphaMissense predicts likely benign (score 0.0793) — an in-silico prediction, not a clinical call.

COL4A3 p.Pro1109Ser

c.3325C>T · rs55816283 · VCV254993

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0793 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.694%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

kidney disorder

Computational evidence

Protein change
AlphaMissense	0.0793	likely benign
REVEL	0.517	indeterminate
SaProt	LLR -8.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 0.32, phastCons 0.36
Regional constraint	o/e 0.84	unconstrained · MANE · 58 kb · p 2.1e-11 · regional, not allelic
Overall
CADD	18.81	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 0.694% European (non-Finnish) · 8,189/1,179,986 alleles

Filtering AF 0.681% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.676%

Overall 0.601% 9,701/1,613,784 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.19%	84
European (non-Finnish)grpmax	0.694%	144
Remaining individualsnot grpmax-eligible	0.543%	184
Middle Eastern	0.413%	242
South Asian	0.381%	262
Admixed American	0.31%	323
Finnishnot grpmax-eligible	0.272%	368
African / African-American	0.119%	843

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: COL4A3
Protein: p.Pro1109Ser
Coding: c.3325C>T
MANE Select: NM_000091
dbSNP: rs55816283
Type: single nucleotide variant
Location: chr2:227293305 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 48.64 · 2 PDB
Residue 1109: the 'triple-helical region' region; the 'disordered' region

Full COL4A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

kidney disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Alport syndrome

Similar variants

COL4A3 p.Pro1109= Likely benign ★ same residue
COL4A3 p.Pro1109Arg Uncertain significance ★ ⚠ same residue
COL4A3 p.Pro1109Leu Uncertain significance ★ ⚠ same residue
COL4A3 c.1114+2T>C Pathogenic/Likely pathogenic ★★ same condition
COL4A3 c.1408+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A3 c.1408+1G>C Pathogenic/Likely pathogenic ★★ same condition
COL4A3 c.1504+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A3 c.1927+1G>A 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/col4a3-p-pro1109ser (accessed [today's date]).

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