Is COL4A2 p.Pro541= (c.1623C>T) pathogenic?

COL4A2 p.Pro541= (c.1623C>T) is classified Conflicting classifications of pathogenicity in COL4A2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-11-14). Ultra-rare (popmax 0.0285%, sas); Associated with COL4A2-related disorder.

What condition is associated with COL4A2 p.Pro541= (c.1623C>T)?

COL4A2 p.Pro541= (c.1623C>T) is associated with COL4A2-related disorder (ClinVar).

How common is COL4A2 p.Pro541= (c.1623C>T) in the general population?

COL4A2 p.Pro541= (c.1623C>T) is ultra-rare (popmax 0.0285%, sas) (gnomAD).

COL4A2 p.Pro541=

c.1623C>T · rs567530451 · VCV2634417

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0285%, sas)

Conditions

COL4A2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8	GERP -2.8
Overall
CADD	0.483	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0285% South Asian · 26/91,084 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0171%

Overall 0.00235% 38/1,614,246 alleles · ultra-rare exomes 33/1,461,894 · genomes 5/152,352 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0285%	3,503
East Asian	0.00668%	14,963
Remaining individualsnot grpmax-eligible	0.0048%	20,837
Admixed American	0.00333%	30,015
African / African-American	0.00266%	37,534
European (non-Finnish)	0.000169%	590,019

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: COL4A2
Protein: p.Pro541=
Coding: c.1623C>T
MANE Select: NM_001846
dbSNP: rs567530451
Type: single nucleotide variant
Location: chr13:110462140 (GRCh38)
Gene constraint: LOEUF 0.618 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 47.97 · 4 PDB
Residue 541: the 'triple-helical region' region; the 'disordered' region

Full COL4A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

COL4A2-related disorder

Similar variants

COL4A2 p.Gly1389Arg Pathogenic/Likely pathogenic ★★ same condition
COL4A2 p.Arg1069Gln Uncertain significance ★★ ⚠ same condition
COL4A2 p.Gly1622Arg Uncertain significance ★★ ⚠ same condition
COL4A2 p.Glu92Ter Likely pathogenic ★ same condition
COL4A2 p.Gly539Ser Likely pathogenic ★ ⚠ same condition
COL4A2 p.Gly872Arg Likely pathogenic ★ same condition
COL4A2 c.1776+1G>A Conflicting classifications of pathogenicity ★ same condition
COL4A2 c.3562+5G>A Uncertain significance ★ 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/col4a2-p-pro541 (accessed [today's date]).

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