Is COL4A2 p.Pro718Ser (c.2152C>T) pathogenic?

COL4A2 p.Pro718Ser (c.2152C>T) is classified Benign in COL4A2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0828); Common (popmax 32.9%, mid) — too common for a highly-penetrant pathogenic allele; Associated with brain small vessel disease 2A, autosomal dominant.

What condition is associated with COL4A2 p.Pro718Ser (c.2152C>T)?

COL4A2 p.Pro718Ser (c.2152C>T) is associated with brain small vessel disease 2A, autosomal dominant (ClinVar).

What do computational predictors say about COL4A2 p.Pro718Ser (c.2152C>T)?

AlphaMissense predicts likely benign (score 0.0828) — an in-silico prediction, not a clinical call.

COL4A2 p.Pro718Ser

Q: How common is COL4A2 p.Pro718Ser (c.2152C>T) in the general population?

COL4A2 p.Pro718Ser (c.2152C>T) is common (popmax 32.9%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2152C>T · rs9583500 · VCV311145

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0828 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 32.9%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

brain small vessel disease 2A, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.0828	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -7.60	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 2.6	GERP 1.4, phastCons 0.98
Regional constraint	o/e 0.80	unconstrained · MANE · 62 kb · p 6e-16 · regional, not allelic
Overall
CADD	16.37	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 32.9% Middle Eastern · 1,952/5,936 alleles

Filtering AF 32.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 32.1%

Overall 19.9% 319,247/1,602,244 alleles · common exomes 284,844/1,450,182 · genomes 34,403/152,062 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	32.9%	3
African / African-American	32.6%	3
Ashkenazi Jewishnot grpmax-eligible	30.5%	3
Amishnot grpmax-eligible	25.1%	4
Remaining individualsnot grpmax-eligible	20.6%	5
European (non-Finnish)	20.5%	5
Finnishnot grpmax-eligible	17.9%	6
Admixed American	14.3%	7
South Asian	11%	9
East Asian	1.15%	87

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.Pro718Ser
Coding: c.2152C>T
MANE Select: NM_001846
dbSNP: rs9583500
Type: single nucleotide variant
Location: chr13:110469273 (GRCh38)
Gene constraint: LOEUF 0.618 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 47.97 · 4 PDB
Residue 718: a UniProt-annotated variant site (does not affect col4a2 and col4a1 secretion); 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 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
COL4A2 p.Arg1617Gln 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-pro718ser (accessed [today's date]).

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