Is COL1A2 p.Pro1362Ser (c.4084C>T) pathogenic?

COL1A2 p.Pro1362Ser (c.4084C>T) is classified Uncertain significance in COL1A2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-04-27). AlphaMissense: likely benign (0.1592); Ultra-rare (popmax 0.0117%, amr); Associated with Cardiovascular phenotype.

What condition is associated with COL1A2 p.Pro1362Ser (c.4084C>T)?

COL1A2 p.Pro1362Ser (c.4084C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is COL1A2 p.Pro1362Ser (c.4084C>T) in the general population?

COL1A2 p.Pro1362Ser (c.4084C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about COL1A2 p.Pro1362Ser (c.4084C>T)?

AlphaMissense predicts likely benign (score 0.1592) — an in-silico prediction, not a clinical call.

COL1A2 p.Pro1362Ser

c.4084C>T · rs755358364 · VCV636431

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1592 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1592	likely benign
REVEL	0.709	pathogenic-leaning
SaProt	LLR -9.64	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,663 bp · p 0.64 · regional, not allelic
Overall
CADD	24.8	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 0.0117% Admixed American · 7/59,980 alleles

Filtering AF 0.00544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00229% 37/1,613,732 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,569
European (non-Finnish)	0.00237%	42,141
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-American	0.00134%	74,858

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: COL1A2
Protein: p.Pro1362Ser
Coding: c.4084C>T
MANE Select: NM_000089
dbSNP: rs755358364
Type: single nucleotide variant
Location: chr7:94430376 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 55.02 · 5 PDB
Residue 1362: the fibrillar collagen nc1 domain; a disulfide bond

Full COL1A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COL1A2 c.2565+1G>A Pathogenic ★★ same condition
COL1A2 p.Ala1119Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
COL1A2 p.Gly259Ser Pathogenic/Likely pathogenic ★★ same condition
COL1A2 p.Gly907Ser Pathogenic/Likely pathogenic ★★ same condition
COL1A2 c.1251+2T>G Uncertain significance ★★ same condition
COL1A2 c.1404+4A>C Uncertain significance ★★ same condition
COL1A2 c.792+4A>T Uncertain significance ★★ same condition
COL1A2 p.Ala1035Thr 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/col1a2-p-pro1362ser (accessed [today's date]).

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