Is COL3A1 p.Ser196Pro (c.586T>C) pathogenic?

COL3A1 p.Ser196Pro (c.586T>C) is classified Uncertain significance in COL3A1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-22). AlphaMissense: likely benign (0.1375); Very rare (popmax 0.00167%, amr); Associated with Ehlers-Danlos syndrome.

What condition is associated with COL3A1 p.Ser196Pro (c.586T>C)?

COL3A1 p.Ser196Pro (c.586T>C) is associated with Ehlers-Danlos syndrome, Ehlers-Danlos syndrome, vascular type, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is COL3A1 p.Ser196Pro (c.586T>C) in the general population?

COL3A1 p.Ser196Pro (c.586T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about COL3A1 p.Ser196Pro (c.586T>C)?

AlphaMissense predicts likely benign (score 0.1375) — an in-silico prediction, not a clinical call.

COL3A1 p.Ser196Pro

c.586T>C · rs751350498 · VCV199712

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1375 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ehlers-Danlos syndrome

Computational evidence

Protein change
AlphaMissense	0.1375	likely benign
REVEL	0.247	benign-leaning
SaProt	LLR -6.24	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 0.54	GERP 0.83, phastCons 0.33
Regional constraint	o/e 0.68	unconstrained · MANE · 12 kb · p 4.3e-17 · regional, not allelic
Overall
CADD	17.55	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 0.00167% Admixed American · 1/59,730 alleles

Filtering AF 0.000771% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000611%

Overall 0.001% 16/1,600,294 alleles · very rare exomes 14/1,448,190 · genomes 2/152,104 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,730
European (non-Finnish)	0.00128%	77,898

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: COL3A1
Protein: p.Ser196Pro
Coding: c.586T>C
MANE Select: NM_000090
dbSNP: rs751350498
Type: single nucleotide variant
Location: chr2:188988593 (GRCh38)
Gene constraint: LOEUF 0.291 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.98 · 11 PDB
Residue 196: the 'disordered' region; the 'triple-helical region' region

Full COL3A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Ehlers-Danlos syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ehlers-Danlos syndrome, vascular type familial thoracic aortic aneurysm and aortic dissection

Similar variants

COL3A1 p.Ser196= Likely benign ★ same residue
COL3A1 c.1051-1G>C Likely pathogenic ★★ same condition
COL3A1 c.1294-1G>A Pathogenic/Likely pathogenic ★★ same condition
COL3A1 c.1347+1G>A Pathogenic ★★ same condition
COL3A1 c.1348-2A>G Pathogenic/Likely pathogenic ★★ same condition
COL3A1 c.1662+1G>A Pathogenic ★★ same condition
COL3A1 c.1663-1G>A Likely pathogenic ★★ same condition
COL3A1 c.1869+1G>C 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/col3a1-p-ser196pro (accessed [today's date]).

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