Is COL2A1 p.Arg515His (c.1544G>A) pathogenic?

COL2A1 p.Arg515His (c.1544G>A) is classified Uncertain significance in COL2A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-11). AlphaMissense: likely pathogenic (0.5961); Very rare (popmax 0.00113%, nfe).

How common is COL2A1 p.Arg515His (c.1544G>A) in the general population?

COL2A1 p.Arg515His (c.1544G>A) is very rare (popmax 0.00113%, nfe) (gnomAD).

What do computational predictors say about COL2A1 p.Arg515His (c.1544G>A)?

AlphaMissense predicts likely pathogenic (score 0.5961) — an in-silico prediction, not a clinical call.

COL2A1 p.Arg515His

c.1544G>A · rs1326204674 · VCV1300304

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5961 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00113%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5961	likely pathogenic
REVEL	0.692	pathogenic-leaning
SaProt	LLR -11.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 21 kb · p 2.4e-45 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00113% European (non-Finnish) · 13/1,147,030 alleles

Filtering AF 0.000632% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000487%

Overall 0.00103% 16/1,551,556 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00334%	29,919
Remaining individualsnot grpmax-eligible	0.00166%	60,082
European (non-Finnish)grpmax	0.00113%	88,233

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.Arg515His
Coding: c.1544G>A
MANE Select: NM_001844
dbSNP: rs1326204674
Type: single nucleotide variant
Location: chr12:47985949 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 515: the 'disordered' region; the 'triple-helical region' region

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

Similar variants

COL2A1 p.Arg515Cys Uncertain significance ★★ ⚠ same residue
COL2A1 p.Arg515= Likely benign ★★ same residue
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
COL2A1 c.1221+1G>A Pathogenic ★★ same type
COL2A1 c.1222-2A>G Pathogenic ★★ same type
COL2A1 c.1365+1G>A 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-arg515his (accessed [today's date]).

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