Is COL18A1 p.Pro765Leu (c.2294C>T) pathogenic?

COL18A1 p.Pro765Leu (c.2294C>T) is classified Uncertain significance in COL18A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-06). AlphaMissense: likely benign (0.1193); Ultra-rare (popmax 0.0814%, sas); Associated with Inborn genetic diseases.

What condition is associated with COL18A1 p.Pro765Leu (c.2294C>T)?

COL18A1 p.Pro765Leu (c.2294C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL18A1 p.Pro765Leu (c.2294C>T) in the general population?

COL18A1 p.Pro765Leu (c.2294C>T) is ultra-rare (popmax 0.0814%, sas) (gnomAD).

What do computational predictors say about COL18A1 p.Pro765Leu (c.2294C>T)?

AlphaMissense predicts likely benign (score 0.1193) — an in-silico prediction, not a clinical call.

COL18A1 p.Pro765Leu

c.2294C>T · rs557802919 · VCV1525152

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1193 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0814%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1193	likely benign
REVEL	0.298	indeterminate
SaProt	LLR -10.03	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
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	24.2	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1180L vs ClinVar P765L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0814% South Asian · 69/84,722 alleles

Filtering AF 0.066% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0603%

Overall 0.00666% 104/1,561,502 alleles · ultra-rare exomes 95/1,409,176 · genomes 9/152,326 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0814%	1,228
East Asian	0.00963%	10,387
Remaining individualsnot grpmax-eligible	0.00495%	20,197
African / African-American	0.00272%	36,766
European (non-Finnish)	0.00217%	46,153
Admixed American	0.00191%	52,368

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.Pro765Leu
Coding: c.2294C>T
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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COL18A1 p.Pro765= Likely benign ★★ same residue
COL18A1 p.Pro765Gln Uncertain significance ★ ⚠ same residue
COL18A1 c.107-12077C>T Uncertain significance ★★ ⚠ same condition
COL18A1 p.Ala1123Thr Uncertain significance ★★ ⚠ same condition
COL18A1 p.Ala115Val Uncertain significance ★★ ⚠ same condition
COL18A1 p.Ala157Thr Uncertain significance ★★ ⚠ same condition
COL18A1 p.Ala208Val Uncertain significance ★★ ⚠ same condition
COL18A1 p.Ala378Thr 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/col18a1-p-pro765leu (accessed [today's date]).

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