Is COL4A4 p.Arg97Cys (c.289C>T) pathogenic?

COL4A4 p.Arg97Cys (c.289C>T) is classified Conflicting classifications of pathogenicity in COL4A4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-01-17). AlphaMissense: likely benign (0.0983); Very rare (popmax 0.00891%, eas); Associated with COL4A4-related disorder.

What condition is associated with COL4A4 p.Arg97Cys (c.289C>T)?

COL4A4 p.Arg97Cys (c.289C>T) is associated with COL4A4-related disorder (ClinVar).

How common is COL4A4 p.Arg97Cys (c.289C>T) in the general population?

COL4A4 p.Arg97Cys (c.289C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about COL4A4 p.Arg97Cys (c.289C>T)?

AlphaMissense predicts likely benign (score 0.0983) — an in-silico prediction, not a clinical call.

COL4A4 p.Arg97Cys

c.289C>T · rs202096172 · VCV2199545

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0983 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

COL4A4-related disorder

Computational evidence

Protein change
AlphaMissense	0.0983	likely benign
REVEL	0.418	indeterminate
SaProt	LLR -8.66	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 -0.66	GERP -3.4
Regional constraint	o/e 0.91	unconstrained · MANE · 140 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	18.45	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 0.00891% East Asian · 4/44,888 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00297% 48/1,613,930 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,222
Remaining individualsnot grpmax-eligible	0.008%	12,496
African / African-American	0.00534%	18,722
South Asian	0.00439%	22,768
Admixed American	0.00333%	29,993
European (non-Finnish)	0.00246%	40,690

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.Arg97Cys
Coding: c.289C>T
MANE Select: NM_000092
dbSNP: rs202096172
Type: single nucleotide variant
Location: chr2:227121052 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 97: the 'disordered' region; the 'triple-helical region' region

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

Disease context

COL4A4-related disorder

Similar variants

COL4A4 p.Arg97His Uncertain significance ★★ ⚠ same residue
COL4A4 p.Arg97= Likely benign ★★ same residue
COL4A4 c.1099+1G>A Pathogenic ★★ same condition
COL4A4 c.1623+5G>T Likely pathogenic ★★ same condition
COL4A4 c.3214+2T>A Likely pathogenic ★★ same condition
COL4A4 c.328-1G>A Likely pathogenic ★★ same condition
COL4A4 p.Arg1377Ter Pathogenic/Likely pathogenic ★★ same condition
COL4A4 p.Gly1008Arg 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-arg97cys (accessed [today's date]).

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