Is COL4A4 p.Arg1006Ser (c.3018A>T) pathogenic?

COL4A4 p.Arg1006Ser (c.3018A>T) is classified Conflicting classifications of pathogenicity in COL4A4 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-23). AlphaMissense: likely benign (0.1387); Rare (popmax 0.212%, sas); Associated with autosomal recessive Alport syndrome.

What condition is associated with COL4A4 p.Arg1006Ser (c.3018A>T)?

COL4A4 p.Arg1006Ser (c.3018A>T) is associated with autosomal recessive Alport syndrome, Alport syndrome, hematuria, benign familial (ClinVar).

How common is COL4A4 p.Arg1006Ser (c.3018A>T) in the general population?

COL4A4 p.Arg1006Ser (c.3018A>T) is rare (popmax 0.212%, sas) (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.Arg1006Ser (c.3018A>T)?

AlphaMissense predicts likely benign (score 0.1387) — an in-silico prediction, not a clinical call.

COL4A4 p.Arg1006Ser

c.3018A>T · rs531161419 · VCV726280

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1387 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.212%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive Alport syndrome

Computational evidence

Protein change
AlphaMissense	0.1387	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -5.43	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 1.4	GERP -0.69, phastCons 0.94
Regional constraint	o/e 0.91	unconstrained · MANE · 140 kb · p 1.4e-05 · regional, not allelic
Overall
CADD	7.284	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 0.212% South Asian · 193/91,070 alleles

Filtering AF 0.187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.178%

Overall 0.0134% 217/1,614,150 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.212%	472
Remaining individualsnot grpmax-eligible	0.0368%	2,718
European (non-Finnish)	8.47e-05%	1,180,008

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.Arg1006Ser
Coding: c.3018A>T
MANE Select: NM_000092
dbSNP: rs531161419
Type: single nucleotide variant
Location: chr2:227051109 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.03 · 2 PDB
Residue 1006: the 'triple-helical region' region; the 'disordered' region

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

Disease context

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

Also linked: Alport syndrome hematuria, benign familial

For Alport syndrome (Orphanet):

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

Similar variants

COL4A4 c.1030-2A>C Likely pathogenic ★★ same condition
COL4A4 c.1099+1G>T Pathogenic/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.1459+1G>A 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

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-arg1006ser (accessed [today's date]).

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