Is COL4A2 p.Pro436= (c.1308C>T) pathogenic?

COL4A2 p.Pro436= (c.1308C>T) is classified Benign in COL4A2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-29). Low-frequency (popmax 3.07%, afr); Associated with brain small vessel disease 2A, autosomal dominant.

What condition is associated with COL4A2 p.Pro436= (c.1308C>T)?

COL4A2 p.Pro436= (c.1308C>T) is associated with brain small vessel disease 2A, autosomal dominant (ClinVar).

How common is COL4A2 p.Pro436= (c.1308C>T) in the general population?

COL4A2 p.Pro436= (c.1308C>T) is low-frequency (popmax 3.07%, afr) (gnomAD).

COL4A2 p.Pro436=

c.1308C>T · rs78615289 · VCV311123

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.07%, afr)

Conditions

brain small vessel disease 2A, autosomal dominant

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 -1	GERP -2.5
Overall
CADD	2.464	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.07% African / African-American · 2,307/75,026 alleles

Filtering AF 2.97% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.93%

Overall 0.166% 2,673/1,613,898 alleles · low-frequency exomes 1,385/1,461,626 · genomes 1,288/152,272 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.07%	33
Middle Eastern	0.38%	263
Remaining individualsnot grpmax-eligible	0.269%	372
Admixed American	0.158%	632
South Asian	0.0165%	6,072
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,802
European (non-Finnish)	0.00534%	18,729

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.Pro436=
Coding: c.1308C>T
MANE Select: NM_001846
dbSNP: rs78615289
Type: single nucleotide variant
Location: chr13:110450423 (GRCh38)
Gene constraint: LOEUF 0.618 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 47.97 · 4 PDB
Residue 436: the 'triple-helical region' region; the 'disordered' region

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

Disease context

brain small vessel disease 2A, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COL4A2 p.Pro436Leu Likely benign ★ same residue
COL4A2 c.361-1G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A2 p.Gly619Asp Likely pathogenic ★★ same condition
COL4A2 c.2425+3G>A Uncertain significance ★★ same condition
COL4A2 p.Ala370Pro Uncertain significance ★★ ⚠ same condition
COL4A2 p.Ala95Asp Uncertain significance ★★ ⚠ same condition
COL4A2 p.Arg1069Gln Uncertain significance ★★ ⚠ same condition
COL4A2 p.Arg1069Trp 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-pro436 (accessed [today's date]).

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