Is COL1A2 p.Ala336= (c.1008C>T) pathogenic?

COL1A2 p.Ala336= (c.1008C>T) is classified Conflicting classifications of pathogenicity in COL1A2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-13). Rare (popmax 0.105%, afr); Associated with Ehlers-Danlos syndrome, classic type, 1.

What condition is associated with COL1A2 p.Ala336= (c.1008C>T)?

COL1A2 p.Ala336= (c.1008C>T) is associated with Ehlers-Danlos syndrome, classic type, 1, osteogenesis imperfecta type 1 (ClinVar).

How common is COL1A2 p.Ala336= (c.1008C>T) in the general population?

COL1A2 p.Ala336= (c.1008C>T) is rare (popmax 0.105%, afr) (gnomAD).

How is Classical Ehlers-Danlos syndrome inherited?

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

COL1A2 p.Ala336=

c.1008C>T · rs138357977 · VCV498647

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.105%, afr)

Conditions

Ehlers-Danlos syndrome, classic type, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5	GERP -4.4
Overall
CADD	6.895	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.105% African / African-American · 79/75,014 alleles

Filtering AF 0.0866% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0797%

Overall 0.00694% 112/1,614,090 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.105%	950
Remaining individualsnot grpmax-eligible	0.0192%	5,209
Admixed American	0.0167%	6,002
East Asian	0.00223%	44,880
South Asian	0.0022%	45,535
Finnishnot grpmax-eligible	0.00156%	64,018
European (non-Finnish)	0.000593%	168,573

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.Ala336=
Coding: c.1008C>T
MANE Select: NM_000089
dbSNP: rs138357977
Type: single nucleotide variant
Location: chr7:94409794 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 55.02 · 5 PDB
Residue 336: 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.Ala336Ser Uncertain significance ★ ⚠ 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
COL1A2 c.226-2A>G Pathogenic/Likely 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-ala336 (accessed [today's date]).

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