Is COL1A2 p.Pro116Thr (c.346C>A) pathogenic?

COL1A2 p.Pro116Thr (c.346C>A) is classified Uncertain significance in COL1A2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.071); Ultra-rare (popmax 0.0417%, sas); Associated with Ehlers-Danlos syndrome, classic type, 1.

What condition is associated with COL1A2 p.Pro116Thr (c.346C>A)?

COL1A2 p.Pro116Thr (c.346C>A) is associated with Ehlers-Danlos syndrome, classic type, 1, osteogenesis imperfecta type 1 (ClinVar).

How common is COL1A2 p.Pro116Thr (c.346C>A) in the general population?

COL1A2 p.Pro116Thr (c.346C>A) is ultra-rare (popmax 0.0417%, sas) (gnomAD).

How is Classical Ehlers-Danlos syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about COL1A2 p.Pro116Thr (c.346C>A)?

AlphaMissense predicts likely benign (score 0.071) — an in-silico prediction, not a clinical call.

COL1A2 p.Pro116Thr

c.346C>A · rs532334520 · VCV3230286

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.071 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0417%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Ehlers-Danlos syndrome, classic type, 1

Computational evidence

Protein change
AlphaMissense	0.071	likely benign
REVEL	0.376	indeterminate
SaProt	LLR -9.09	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 6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.09 · regional, not allelic
Overall
CADD	22.3	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 0.0417% South Asian · 38/91,066 alleles

Filtering AF 0.0312% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0276%

Overall 0.00273% 44/1,614,058 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0417%	2,396
East Asian	0.00223%	44,882
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000339%	294,996

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.Pro116Thr
Coding: c.346C>A
MANE Select: NM_000089
dbSNP: rs532334520
Type: single nucleotide variant
Location: chr7:94404714 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 55.02 · 5 PDB
Residue 116: the 'disordered' region

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

Disease context

Ehlers-Danlos syndrome, classic type, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: osteogenesis imperfecta type 1

For Classical Ehlers-Danlos syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

COL1A2 p.Pro116Ser Uncertain significance ★ ⚠ same residue
COL1A2 p.Pro116= Likely benign ★ same residue
COL1A2 c.1197+5G>A Pathogenic ★★ same condition
COL1A2 c.1503+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL1A2 c.1503+1G>C Pathogenic ★★ same condition
COL1A2 c.1557+3A>G Pathogenic ★★ same condition
COL1A2 c.2026-2A>G Pathogenic/Likely pathogenic ★★ same condition
COL1A2 c.2133+6T>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/col1a2-p-pro116thr (accessed [today's date]).

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