Is COL4A1 p.Pro613Ala (c.1837C>G) pathogenic?

COL4A1 p.Pro613Ala (c.1837C>G) is classified Uncertain significance in COL4A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-01-24). AlphaMissense: likely benign (0.0633); Very rare (popmax 0.00669%, eas); Associated with brain small vessel disease 1 with or without ocular anomalies.

How common is COL4A1 p.Pro613Ala (c.1837C>G) in the general population?

COL4A1 p.Pro613Ala (c.1837C>G) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about COL4A1 p.Pro613Ala (c.1837C>G)?

AlphaMissense predicts likely benign (score 0.0633) — an in-silico prediction, not a clinical call.

COL4A1 p.Pro613Ala

Q: What condition is associated with COL4A1 p.Pro613Ala (c.1837C>G)?

COL4A1 p.Pro613Ala (c.1837C>G) is associated with brain small vessel disease 1 with or without ocular anomalies, COL4A1-related disorder (ClinVar).

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.1837C>G · rs1432737813 · VCV1699185

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0633 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

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	0.0633	likely benign
REVEL	0.372	indeterminate
SaProt	LLR -8.48	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 9.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 30 kb · p 1.5e-10 · regional, not allelic
Overall
CADD	19.64	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 0.00669% East Asian · 3/44,874 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000205% 3/1,461,444 alleles · very 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.Pro613Ala
Coding: c.1837C>G
MANE Select: NM_001845
dbSNP: rs1432737813
Type: single nucleotide variant
Location: chr13:110186445 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.43 · 4 PDB
Residue 613: 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: COL4A1-related disorder

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

Inheritance: Autosomal dominant

Similar variants

COL4A1 p.Pro613Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
COL4A1 p.Pro613Ser Uncertain significance ★★ ⚠ same residue
COL4A1 p.Pro613Leu Uncertain significance ★ ⚠ same residue
COL4A1 c.1085-2A>G Likely pathogenic ★★ same condition
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

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-pro613ala (accessed [today's date]).

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