Is COL4A3 p.Ser2Arg (c.6C>G) pathogenic?

COL4A3 p.Ser2Arg (c.6C>G) is classified Uncertain significance in COL4A3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-22). AlphaMissense: likely benign (0.0855); Very rare (popmax 0.00138%, afr).

How common is COL4A3 p.Ser2Arg (c.6C>G) in the general population?

COL4A3 p.Ser2Arg (c.6C>G) is very rare (popmax 0.00138%, afr) (gnomAD).

What do computational predictors say about COL4A3 p.Ser2Arg (c.6C>G)?

AlphaMissense predicts likely benign (score 0.0855) — an in-silico prediction, not a clinical call.

COL4A3 p.Ser2Arg

c.6C>G · VCV3370980

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0855 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00138%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0855	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -6.01	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 0.41	GERP 2.1
Regional constraint	o/e 1.09	unconstrained · MANE · 89 kb · p 0.088 · regional, not allelic
Overall
CADD	7.216	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 0.00138% African / African-American · 1/72,270 alleles

Filtering AF 0.000301% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000217%

Overall 0.000588% 9/1,529,896 alleles · very rare exomes 8/1,377,794 · genomes 1/152,102 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00138%	72,270
European (non-Finnish)	0.000699%	143,128

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: COL4A3
Protein: p.Ser2Arg
Coding: c.6C>G
MANE Select: NM_000091
Type: single nucleotide variant
Location: chr2:227164732 (GRCh38)
Gene constraint: LOEUF 0.709 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 48.64 · 2 PDB

Full COL4A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL4A3 p.Ser2= Likely benign ★ same residue
COL4A3 c.1114+1G>A Likely pathogenic ★★ same type
COL4A3 c.1114+2T>C Pathogenic/Likely pathogenic ★★ same type
COL4A3 c.1408+1G>A Pathogenic/Likely pathogenic ★★ same type
COL4A3 c.1408+1G>C Pathogenic/Likely pathogenic ★★ same type
COL4A3 c.1504+1G>A Pathogenic/Likely pathogenic ★★ same type
COL4A3 c.1927+1G>A Likely pathogenic ★★ same type
COL4A3 c.2020+1G>T 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/col4a3-p-ser2arg (accessed [today's date]).

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