Is COL2A1 p.Arg53Gln (c.158G>A) pathogenic?

COL2A1 p.Arg53Gln (c.158G>A) is classified Likely benign in COL2A1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0698); Very rare (popmax 0.00534%, afr); Associated with intellectual disability.

What condition is associated with COL2A1 p.Arg53Gln (c.158G>A)?

COL2A1 p.Arg53Gln (c.158G>A) is associated with intellectual disability (ClinVar).

How common is COL2A1 p.Arg53Gln (c.158G>A) in the general population?

COL2A1 p.Arg53Gln (c.158G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about COL2A1 p.Arg53Gln (c.158G>A)?

AlphaMissense predicts likely benign (score 0.0698) — an in-silico prediction, not a clinical call.

COL2A1 p.Arg53Gln

c.158G>A · rs370821294 · VCV975372

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0698 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.0698	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -8.73	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 1.4	GERP -2.2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 7,716 bp · p 0.0078 · regional, not allelic
Overall
CADD	18.09	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 · 4/74,886 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00291% 47/1,613,890 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0141%	7,106
African / African-Americangrpmax	0.00534%	18,722
East Asian	0.00445%	22,448
South Asian	0.00439%	22,769
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	0.00212%	47,200
Admixed American	0.00167%	60,000

Finnish 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.Arg53Gln
Coding: c.158G>A
MANE Select: NM_001844
dbSNP: rs370821294
Type: single nucleotide variant
Location: chr12:48000053 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 53: a β-strand; the vwfc domain

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

Disease context

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COL2A1 p.Arg53Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
COL2A1 p.Arg53Leu Uncertain significance ★ ⚠ same residue
COL2A1 p.Arg53Trp Likely benign ★ ⚠ same residue
COL2A1 p.Arg53fs Pathogenic ★ same residue
COL2A1 p.Ala1103Gly Conflicting classifications of pathogenicity ★ ⚠ same condition
COL2A1 c.1023+1G>A Pathogenic ★★ same type
COL2A1 c.1024-2A>C Pathogenic ★★ same type
COL2A1 c.1069-2A>G Pathogenic/Likely pathogenic ★★ same type

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-arg53gln (accessed [today's date]).

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