Is COL18A1 p.Pro765Gln (c.2294C>A) pathogenic?

COL18A1 p.Pro765Gln (c.2294C>A) is classified Uncertain significance in COL18A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-13). AlphaMissense: likely benign (0.1652); Very rare (popmax 0.00121%, nfe).

How common is COL18A1 p.Pro765Gln (c.2294C>A) in the general population?

COL18A1 p.Pro765Gln (c.2294C>A) is very rare (popmax 0.00121%, nfe) (gnomAD).

What do computational predictors say about COL18A1 p.Pro765Gln (c.2294C>A)?

AlphaMissense predicts likely benign (score 0.1652) — an in-silico prediction, not a clinical call.

COL18A1 p.Pro765Gln

c.2294C>A · rs557802919 · VCV1367196

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1652 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00121%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1652	likely benign
REVEL	0.343	indeterminate
SaProt	LLR -9.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 107 kb · p 4.9e-06 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

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

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1180Q vs ClinVar P765Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00121% European (non-Finnish) · 14/1,153,838 alleles

Filtering AF 0.000704% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000551%

Overall 0.000897% 14/1,561,504 alleles · very rare exomes 14/1,409,178 · genomes 0/152,326 · joint denominator

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: COL18A1
Protein: p.Pro765Gln
Coding: c.2294C>A
MANE Select: NM_001379500
dbSNP: rs557802919
Type: single nucleotide variant
Location: chr21:45493517 (GRCh38)
Gene constraint: LOEUF 1.001 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.77 · 9 PDB
Residue 1180 UniProt numbering: the 'triple-helical region 5 (col5)' region; the 'disordered' region

Full COL18A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL18A1 p.Pro765Leu Uncertain significance ★★ ⚠ same residue
COL18A1 p.Pro765= Likely benign ★★ same residue
COL18A1 c.1897-2A>G Likely pathogenic ★★ same type
COL18A1 c.2157+1G>A Likely pathogenic ★★ same type
COL18A1 c.2577+1G>A Pathogenic/Likely pathogenic ★★ same type
COL18A1 c.3013+3A>C Likely pathogenic ★★ same type
COL18A1 c.3809+2T>C Pathogenic ★★ same type
COL18A1 c.798+1G>T 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/col18a1-p-pro765gln (accessed [today's date]).

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