Is COL4A3 p.Pro723Ser (c.2167C>T) pathogenic?

COL4A3 p.Pro723Ser (c.2167C>T) is classified Uncertain significance in COL4A3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-09). AlphaMissense: likely benign (0.0923); Very rare (popmax 0.00503%, amr); Associated with autosomal dominant Alport syndrome.

What condition is associated with COL4A3 p.Pro723Ser (c.2167C>T)?

COL4A3 p.Pro723Ser (c.2167C>T) is associated with autosomal dominant Alport syndrome, Alport syndrome 3b, autosomal recessive, hematuria, benign familial, 2 (ClinVar).

How common is COL4A3 p.Pro723Ser (c.2167C>T) in the general population?

COL4A3 p.Pro723Ser (c.2167C>T) is very rare (popmax 0.00503%, amr) (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 COL4A3 p.Pro723Ser (c.2167C>T)?

AlphaMissense predicts likely benign (score 0.0923) — an in-silico prediction, not a clinical call.

COL4A3 p.Pro723Ser

c.2167C>T · VCV3586047

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0923 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00503%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

autosomal dominant Alport syndrome

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.0923	likely benign
REVEL	0.485	indeterminate
SaProt	LLR -8.63	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 58 kb · p 2.1e-11 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00503% Admixed American · 3/59,626 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00224% 36/1,610,546 alleles · very rare exomes 23/1,458,462 · genomes 13/152,084 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.987%	101
Admixed Americangrpmax	0.00503%	19,875
European (non-Finnish)	0.00204%	49,113

Amish 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.Pro723Ser
Coding: c.2167C>T
MANE Select: NM_000091
Type: single nucleotide variant
Location: chr2:227279834 (GRCh38)

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

Disease context

autosomal dominant Alport syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Alport syndrome 3b, autosomal recessive hematuria, benign familial, 2

For Alport syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked dominant
Onset: Adolescent, Adult, Childhood, Elderly

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-pro723ser (accessed [today's date]).

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