Is COL1A2 p.Arg41His (c.122G>A) pathogenic?

COL1A2 p.Arg41His (c.122G>A) is classified Benign/Likely benign in COL1A2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-04-09). AlphaMissense: likely benign (0.1053); Low-frequency (popmax 1.01%, afr); Associated with osteogenesis imperfecta.

What condition is associated with COL1A2 p.Arg41His (c.122G>A)?

COL1A2 p.Arg41His (c.122G>A) is associated with osteogenesis imperfecta, osteogenesis imperfecta type 1, Ehlers-Danlos syndrome, classic type, 1 (ClinVar).

How common is COL1A2 p.Arg41His (c.122G>A) in the general population?

COL1A2 p.Arg41His (c.122G>A) is low-frequency (popmax 1.01%, afr) (gnomAD).

How is Osteogenesis imperfecta inherited?

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

What do computational predictors say about COL1A2 p.Arg41His (c.122G>A)?

AlphaMissense predicts likely benign (score 0.1053) — an in-silico prediction, not a clinical call.

COL1A2 p.Arg41His

c.122G>A · rs139528613 · VCV360944

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1053 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.01%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

osteogenesis imperfecta

Computational evidence

Protein change
AlphaMissense	0.1053	likely benign
REVEL	0.47	indeterminate
SaProt	LLR -9.91	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 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.09 · regional, not allelic
Overall
CADD	28.4	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 1.01% African / African-American · 754/75,016 alleles

Filtering AF 0.946% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.922%

Overall 0.0521% 840/1,613,620 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.01%	99
Remaining individualsnot grpmax-eligible	0.0656%	1,524
Admixed American	0.0267%	3,750
European (non-Finnish)	0.00237%	42,130
Finnishnot grpmax-eligible	0.00156%	64,024

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.Arg41His
Coding: c.122G>A
MANE Select: NM_000089
dbSNP: rs139528613
Type: single nucleotide variant
Location: chr7:94399074 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 55.02 · 5 PDB
Residue 41: the 'disordered' region

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

Disease context

osteogenesis imperfecta — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: osteogenesis imperfecta type 1 Ehlers-Danlos syndrome, classic type, 1 Ehlers-Danlos syndrome, arthrochalasia type, 2

For Osteogenesis imperfecta (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Worldwide)

Similar variants

COL1A2 p.Arg41Cys 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-arg41his (accessed [today's date]).

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