Is COL4A3 p.Pro99Ser (c.295C>T) pathogenic?

COL4A3 p.Pro99Ser (c.295C>T) is classified Uncertain significance in COL4A3 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-05-06). AlphaMissense: likely benign (0.1157); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with COL4A3 p.Pro99Ser (c.295C>T)?

COL4A3 p.Pro99Ser (c.295C>T) is associated with Inborn genetic diseases, Alport syndrome (ClinVar).

How common is COL4A3 p.Pro99Ser (c.295C>T) in the general population?

COL4A3 p.Pro99Ser (c.295C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about COL4A3 p.Pro99Ser (c.295C>T)?

AlphaMissense predicts likely benign (score 0.1157) — an in-silico prediction, not a clinical call.

COL4A3 p.Pro99Ser

c.295C>T · VCV4005385

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1157 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1157	likely benign
REVEL	0.678	pathogenic-leaning
SaProt	LLR -9.06	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 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 89 kb · p 0.088 · regional, not allelic
Overall
CADD	27.1	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 0.00134% African / African-American · 1/74,598 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,612,522 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,598
European (non-Finnish)	0.00017%	589,723

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.Pro99Ser
Coding: c.295C>T
MANE Select: NM_000091
Type: single nucleotide variant
Location: chr2:227244966 (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 99: the 'triple-helical region' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Alport syndrome

Similar variants

COL4A3 p.Pro99Ala 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
COL4A3 c.2020+1G>T Likely pathogenic ★★ same condition
COL4A3 c.2224-2A>G 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-pro99ser (accessed [today's date]).

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