Is COL4A4 p.Pro228Gln (c.683C>A) pathogenic?

COL4A4 p.Pro228Gln (c.683C>A) is classified Conflicting classifications of pathogenicity in COL4A4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.0959); Ultra-rare (popmax 0.0254%, sas).

How common is COL4A4 p.Pro228Gln (c.683C>A) in the general population?

COL4A4 p.Pro228Gln (c.683C>A) is ultra-rare (popmax 0.0254%, sas) (gnomAD).

What do computational predictors say about COL4A4 p.Pro228Gln (c.683C>A)?

AlphaMissense predicts likely benign (score 0.0959) — an in-silico prediction, not a clinical call.

COL4A4 p.Pro228Gln

c.683C>A · rs749481247 · VCV2179256

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0959 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0959	likely benign
REVEL	0.373	indeterminate
SaProt	LLR -8.45	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 9.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 140 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	23.0	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 0.0254% South Asian · 23/90,662 alleles

Filtering AF 0.0172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00168% 27/1,611,882 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0254%	3,942
Remaining individualsnot grpmax-eligible	0.00641%	15,601

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.Pro228Gln
Coding: c.683C>A
MANE Select: NM_000092
dbSNP: rs749481247
Type: single nucleotide variant
Location: chr2:227108843 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 228: the 'triple-helical region' region; the 'disordered' region

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

Similar variants

COL4A4 p.Pro228= Likely benign ★ same residue
COL4A4 p.Pro228fs Pathogenic same residue
COL4A4 c.1030-2A>C Likely pathogenic ★★ same type
COL4A4 c.1099+1G>A Pathogenic ★★ same type
COL4A4 c.1099+1G>T Pathogenic/Likely pathogenic ★★ same type
COL4A4 c.1369+1G>A Pathogenic/Likely pathogenic ★★ same type
COL4A4 c.1370-2A>C Likely pathogenic ★★ same type
COL4A4 c.1459+1G>A 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/col4a4-p-pro228gln (accessed [today's date]).

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