Is COL4A4 p.Pro800Arg (c.2399C>G) pathogenic?

COL4A4 p.Pro800Arg (c.2399C>G) is classified Conflicting classifications of pathogenicity in COL4A4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-09). AlphaMissense: likely benign (0.0869); Very rare (popmax 0.000847%, nfe); Associated with Alport syndrome.

What condition is associated with COL4A4 p.Pro800Arg (c.2399C>G)?

COL4A4 p.Pro800Arg (c.2399C>G) is associated with Alport syndrome (ClinVar).

How common is COL4A4 p.Pro800Arg (c.2399C>G) in the general population?

COL4A4 p.Pro800Arg (c.2399C>G) is very rare (popmax 0.000847%, nfe) (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 COL4A4 p.Pro800Arg (c.2399C>G)?

AlphaMissense predicts likely benign (score 0.0869) — an in-silico prediction, not a clinical call.

COL4A4 p.Pro800Arg

c.2399C>G · rs200714000 · VCV334719

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0869 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Alport syndrome

Computational evidence

Protein change
AlphaMissense	0.0869	likely benign
REVEL	0.647	pathogenic-leaning
SaProt	LLR -9.38	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 140 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	24.8	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 0.000847% European (non-Finnish) · 10/1,180,030 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.0273% 440/1,614,154 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.667%	150
Remaining individualsnot grpmax-eligible	0.0048%	20,837
European (non-Finnish)grpmax	0.000847%	118,003

Finnish 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: COL4A4
Protein: p.Pro800Arg
Coding: c.2399C>G
MANE Select: NM_000092
dbSNP: rs200714000
Type: single nucleotide variant
Location: chr2:227057585 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 800: the 'triple-helical region' region; the 'disordered' region

Full COL4A4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

COL4A4 p.Pro800= Likely benign ★ same residue
COL4A4 c.1030-2A>C Likely pathogenic ★★ same condition
COL4A4 c.1369+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A4 c.1370-2A>C Likely pathogenic ★★ same condition
COL4A4 c.1696+1G>A Likely pathogenic ★★ same condition
COL4A4 c.1696+1G>T Likely pathogenic ★★ same condition
COL4A4 c.1697-1G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A4 c.1803+2T>C Pathogenic/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/col4a4-p-pro800arg (accessed [today's date]).

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