Is COL9A2 p.Pro620Leu (c.1859C>T) pathogenic?

COL9A2 p.Pro620Leu (c.1859C>T) is classified Uncertain significance in COL9A2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.1315); Very rare (popmax 0.00398%, nfe).

How common is COL9A2 p.Pro620Leu (c.1859C>T) in the general population?

COL9A2 p.Pro620Leu (c.1859C>T) is very rare (popmax 0.00398%, nfe) (gnomAD).

What do computational predictors say about COL9A2 p.Pro620Leu (c.1859C>T)?

AlphaMissense predicts likely benign (score 0.1315) — an in-silico prediction, not a clinical call.

COL9A2 p.Pro620Leu

c.1859C>T · rs774470944 · VCV1254289

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1315 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00398%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1315	likely benign
REVEL	0.719	pathogenic-leaning
SaProt	LLR -9.96	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.018 · regional, not allelic
Overall
CADD	32.0	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 0.00398% European (non-Finnish) · 47/1,179,914 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.00297% 48/1,613,870 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00398%	25,105
African / African-American	0.00133%	74,924

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.Pro620Leu
Coding: c.1859C>T
MANE Select: NM_001852
dbSNP: rs774470944
Type: single nucleotide variant
Location: chr1:40301823 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.99 · 4 PDB
Residue 620: a UniProt-annotated variant site (sequence variant); the 'triple-helical region 2 (col2)' region; the 'disordered' region

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

Similar variants

COL9A2 p.Pro620Ser 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
COL9A2 c.1870+5G>C 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-pro620leu (accessed [today's date]).

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