Is COL2A1 p.Arg149His (c.446G>A) pathogenic?

COL2A1 p.Arg149His (c.446G>A) is classified Conflicting classifications of pathogenicity in COL2A1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.159); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with COL2A1 p.Arg149His (c.446G>A)?

COL2A1 p.Arg149His (c.446G>A) is associated with Inborn genetic diseases, spondyloperipheral dysplasia (ClinVar).

How common is COL2A1 p.Arg149His (c.446G>A) in the general population?

COL2A1 p.Arg149His (c.446G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about COL2A1 p.Arg149His (c.446G>A)?

AlphaMissense predicts likely benign (score 0.159) — an in-silico prediction, not a clinical call.

COL2A1 p.Arg149His

c.446G>A · rs763538232 · VCV1186037

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.159 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.159	likely benign
REVEL	0.6	indeterminate
SaProt	LLR -8.60	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 4.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 7,716 bp · p 0.0078 · regional, not allelic
Overall
CADD	25.9	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 0.00534% African / African-American · 4/74,872 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00223% 36/1,613,896 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0608%	1,645
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-Americangrpmax	0.00534%	18,718
Admixed American	0.00333%	29,998
South Asian	0.00329%	30,361
European (non-Finnish)	0.000424%	236,002

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: COL2A1
Protein: p.Arg149His
Coding: c.446G>A
MANE Select: NM_001844
dbSNP: rs763538232
Type: single nucleotide variant
Location: chr12:47997691 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 149: the 'disordered' region

Full COL2A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: spondyloperipheral dysplasia

Similar variants

COL2A1 p.Arg149Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
COL2A1 p.Ala302Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
COL2A1 p.Arg565Cys Pathogenic/Likely pathogenic ★★ same condition
COL2A1 p.Arg653Ter Pathogenic ★★ same condition
COL2A1 p.Arg989Cys Pathogenic/Likely pathogenic ★★ same condition
COL2A1 p.Cys52Ter Pathogenic/Likely pathogenic ★★ same condition
COL2A1 p.Cys86Ter Pathogenic ★★ same condition
COL2A1 p.Gln39Ter 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/col2a1-p-arg149his (accessed [today's date]).

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