Is COL4A1 p.Ala620Pro (c.1858G>C) pathogenic?

COL4A1 p.Ala620Pro (c.1858G>C) is classified Conflicting classifications of pathogenicity in COL4A1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-28). AlphaMissense: likely benign (0.0721); Ultra-rare (popmax 0.0203%, nfe); Associated with brain small vessel disease 1 with or without ocular anomalies.

What condition is associated with COL4A1 p.Ala620Pro (c.1858G>C)?

COL4A1 p.Ala620Pro (c.1858G>C) is associated with brain small vessel disease 1 with or without ocular anomalies, autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (ClinVar).

How common is COL4A1 p.Ala620Pro (c.1858G>C) in the general population?

COL4A1 p.Ala620Pro (c.1858G>C) is ultra-rare (popmax 0.0203%, nfe) (gnomAD).

What do computational predictors say about COL4A1 p.Ala620Pro (c.1858G>C)?

AlphaMissense predicts likely benign (score 0.0721) — an in-silico prediction, not a clinical call.

COL4A1 p.Ala620Pro

Q: How is COL4A1/2-related familial vascular leukoencephalopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1858G>C · rs372803920 · VCV311061

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0721 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0203%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

brain small vessel disease 1 with or without ocular anomalies

Computational evidence

Protein change
AlphaMissense	0.0721	likely benign
REVEL	0.161	moderately benign-leaning
SaProt	LLR -4.36	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 -0.23	GERP -3.5
Regional constraint	o/e 0.79	unconstrained · MANE · 30 kb · p 1.5e-10 · regional, not allelic
Overall
CADD	10.25	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 0.0203% European (non-Finnish) · 240/1,180,042 alleles

Filtering AF 0.0182% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0173%

Overall 0.0154% 249/1,613,632 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0203%	4,917
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-American	0.004%	24,978
Admixed American	0.00333%	30,006

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: COL4A1
Protein: p.Ala620Pro
Coding: c.1858G>C
MANE Select: NM_001845
dbSNP: rs372803920
Type: single nucleotide variant
Location: chr13:110186424 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.43 · 4 PDB
Residue 620: the 'triple-helical region' region; the 'disordered' region

Full COL4A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

brain small vessel disease 1 with or without ocular anomalies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

For COL4A1/2-related familial vascular leukoencephalopathy (Orphanet):

Inheritance: Autosomal dominant

Similar variants

COL4A1 p.Ala620Thr Uncertain significance ★ ⚠ same residue
COL4A1 c.1991-2A>G Likely pathogenic ★★ same condition
COL4A1 c.2458+1G>A Pathogenic ★★ same condition
COL4A1 c.2458+2T>C Pathogenic/Likely pathogenic ★★ same condition
COL4A1 c.3742+1G>A Pathogenic ★★ same condition
COL4A1 c.388-1G>C Pathogenic/Likely pathogenic ★★ same condition
COL4A1 c.4250-1G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A1 c.*32G>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/col4a1-p-ala620pro (accessed [today's date]).

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