Is COL2A1 p.Arg565His (c.1694G>A) pathogenic?

COL2A1 p.Arg565His (c.1694G>A) is classified Conflicting classifications of pathogenicity in COL2A1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-15). AlphaMissense: likely benign (0.2987); Ultra-rare (popmax 0.0164%, mid); Associated with spondylometaphyseal dysplasia.

What condition is associated with COL2A1 p.Arg565His (c.1694G>A)?

COL2A1 p.Arg565His (c.1694G>A) is associated with spondylometaphyseal dysplasia (ClinVar).

How common is COL2A1 p.Arg565His (c.1694G>A) in the general population?

COL2A1 p.Arg565His (c.1694G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about COL2A1 p.Arg565His (c.1694G>A)?

AlphaMissense predicts likely benign (score 0.2987) — an in-silico prediction, not a clinical call.

COL2A1 p.Arg565His

c.1694G>A · rs372182200 · VCV845468

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2987 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

spondylometaphyseal dysplasia

Computational evidence

Protein change
AlphaMissense	0.2987	likely benign
REVEL	0.546	indeterminate
SaProt	LLR -7.74	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 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 21 kb · p 2.4e-45 · regional, not allelic
Overall
CADD	25.1	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00452% 73/1,613,902 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.0117%	8,572
European (non-Finnish)	0.00525%	19,032
South Asian	0.00329%	30,363

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.Arg565His
Coding: c.1694G>A
MANE Select: NM_001844
dbSNP: rs372182200
Type: single nucleotide variant
Location: chr12:47985574 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 565: a UniProt-annotated variant site (in stl1); the 'disordered' region; the 'triple-helical region' region

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

Disease context

spondylometaphyseal dysplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COL2A1 p.Arg565Cys Pathogenic/Likely pathogenic ★★ same residue
COL2A1 p.Arg565Gly Uncertain significance ★ ⚠ same residue
COL2A1 p.Arg565Leu Uncertain significance ★ same residue
COL2A1 p.Arg653Ter Pathogenic ★★ same condition
COL2A1 p.Arg989Cys Pathogenic/Likely pathogenic ★★ same condition
COL2A1 p.Cys86Ter Pathogenic ★★ same condition
COL2A1 p.Arg1270His Conflicting classifications of pathogenicity ★ ⚠ same condition
COL2A1 p.Gly873Val Uncertain significance ★ ⚠ 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-arg565his (accessed [today's date]).

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