Is COL4A1 p.Pro210Ser (c.628C>T) pathogenic?

COL4A1 p.Pro210Ser (c.628C>T) is classified Uncertain significance in COL4A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-08). AlphaMissense: likely benign (0.0837); Ultra-rare (popmax 0.0357%, amr); Associated with brain small vessel disease 1 with or without ocular anomalies.

What condition is associated with COL4A1 p.Pro210Ser (c.628C>T)?

COL4A1 p.Pro210Ser (c.628C>T) is associated with brain small vessel disease 1 with or without ocular anomalies, retinal arterial tortuosity, autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (ClinVar).

How common is COL4A1 p.Pro210Ser (c.628C>T) in the general population?

COL4A1 p.Pro210Ser (c.628C>T) is ultra-rare (popmax 0.0357%, amr) (gnomAD).

What do computational predictors say about COL4A1 p.Pro210Ser (c.628C>T)?

AlphaMissense predicts likely benign (score 0.0837) — an in-silico prediction, not a clinical call.

COL4A1 p.Pro210Ser

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.628C>T · VCV3575750

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0837 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

brain small vessel disease 1 with or without ocular anomalies

Computational evidence

Protein change
AlphaMissense	0.0837	likely benign
REVEL	0.571	indeterminate
SaProt	LLR -8.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 33 kb · p 2.1e-05 · regional, not allelic
Overall
CADD	21.9	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 0.0357% Admixed American · 21/58,902 alleles

Filtering AF 0.0238% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.02%

Overall 0.00131% 21/1,608,914 alleles · ultra-rare

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.Pro210Ser
Coding: c.628C>T
MANE Select: NM_001845
Type: single nucleotide variant
Location: chr13:110209415 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.43 · 4 PDB
Residue 210: a modified residue (3-hydroxyproline); the 'disordered' region; the 'triple-helical region' 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: retinal arterial tortuosity autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome microangiopathy and leukoencephalopathy, pontine, autosomal dominant hemorrhage, intracerebral, susceptibility to

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

Inheritance: Autosomal dominant

Similar variants

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
COL4A1 p.Arg1063Ter 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-pro210ser (accessed [today's date]).

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