Is COL9A2 p.Arg640Ter (c.1918C>T) pathogenic?

COL9A2 p.Arg640Ter (c.1918C>T) is classified Uncertain significance in COL9A2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-06). Very rare (popmax 0.00263%, nfe).

How common is COL9A2 p.Arg640Ter (c.1918C>T) in the general population?

COL9A2 p.Arg640Ter (c.1918C>T) is very rare (popmax 0.00263%, nfe) (gnomAD).

COL9A2 p.Arg640Ter

c.1918C>T · rs747162216 · VCV488982

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00263%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (32 of 32) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP -1, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00263% European (non-Finnish) · 31/1,177,552 alleles

Filtering AF 0.00189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00255% 41/1,610,218 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.011%	9,129
Remaining individualsnot grpmax-eligible	0.00482%	20,753
European (non-Finnish)grpmax	0.00263%	37,986

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: COL9A2
Protein: p.Arg640Ter
Coding: c.1918C>T
MANE Select: NM_001852
dbSNP: rs747162216
Type: single nucleotide variant
Location: chr1:40301334 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.99 · 4 PDB
Residue 640: the 'triple-helical region 1 (col1)' region; a UniProt-annotated variant site (sequence variant); the 'disordered' region

Full COL9A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL9A2 p.Arg640Gln Uncertain significance ★★ ⚠ same residue
COL9A2 p.Arg640Pro Uncertain significance ★ ⚠ same residue
COL9A2 c.186+1G>A Pathogenic/Likely pathogenic ★★ same type
COL9A2 p.Arg136Ter Pathogenic/Likely pathogenic ★★ same type
COL9A2 p.Arg504Ter Pathogenic/Likely pathogenic ★★ same type
COL9A2 c.1107+4A>G Uncertain significance ★★ same type
COL9A2 c.1792+5G>A Uncertain significance ★★ same type
COL9A2 c.1793-9T>A Uncertain significance ★★ 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/col9a2-p-arg640ter (accessed [today's date]).

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