Is COL4A4 p.Arg227Pro (c.680G>C) pathogenic?

COL4A4 p.Arg227Pro (c.680G>C) is classified Uncertain significance in COL4A4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-02). AlphaMissense: likely benign (0.1094); Very rare (popmax 0.00195%, nfe).

How common is COL4A4 p.Arg227Pro (c.680G>C) in the general population?

COL4A4 p.Arg227Pro (c.680G>C) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about COL4A4 p.Arg227Pro (c.680G>C)?

AlphaMissense predicts likely benign (score 0.1094) — an in-silico prediction, not a clinical call.

COL4A4 p.Arg227Pro

c.680G>C · rs368248078 · VCV2414589

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1094 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1094	likely benign
REVEL	0.234	benign-leaning
SaProt	LLR -5.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.21	GERP -2.3, phastCons 0.003
Regional constraint	o/e 0.91	unconstrained · MANE · 140 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	14.01	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 0.00195% European (non-Finnish) · 23/1,178,772 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.00149% 24/1,611,840 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,251
Remaining individualsnot grpmax-eligible	0.0016%	62,390

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.Arg227Pro
Coding: c.680G>C
MANE Select: NM_000092
dbSNP: rs368248078
Type: single nucleotide variant
Location: chr2:227108846 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 227: 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.Arg227Cys Uncertain significance ★★ ⚠ same residue
COL4A4 p.Arg227His Conflicting classifications of pathogenicity ★ ⚠ same residue
COL4A4 p.Arg227= Likely benign ★ 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

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-arg227pro (accessed [today's date]).

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