Is COL18A1 p.Pro366Ser (c.1096C>T) pathogenic?

COL18A1 p.Pro366Ser (c.1096C>T) is classified Uncertain significance in COL18A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-19). AlphaMissense: likely benign (0.0701); Ultra-rare (popmax 0.0334%, mid); Associated with Inborn genetic diseases.

What condition is associated with COL18A1 p.Pro366Ser (c.1096C>T)?

COL18A1 p.Pro366Ser (c.1096C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL18A1 p.Pro366Ser (c.1096C>T) in the general population?

COL18A1 p.Pro366Ser (c.1096C>T) is ultra-rare (popmax 0.0334%, mid) (gnomAD).

What do computational predictors say about COL18A1 p.Pro366Ser (c.1096C>T)?

AlphaMissense predicts likely benign (score 0.0701) — an in-silico prediction, not a clinical call.

COL18A1 p.Pro366Ser

c.1096C>T · rs377028409 · VCV1374838

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0701 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0701	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -9.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.93	GERP -0.24, phastCons 0.002
Regional constraint	o/e 1.10	unconstrained · MANE · 107 kb · p 4.9e-06 · regional, not allelic
Overall
CADD	8.293	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 P781S vs ClinVar P366S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0334% Middle Eastern · 2/5,984 alleles

Filtering AF 0.0125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.00142% 22/1,553,154 alleles · ultra-rare exomes 11/1,400,824 · genomes 11/152,330 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0334%	2,992
African / African-American	0.0205%	4,887
South Asian	0.00237%	42,113
European (non-Finnish)	0.000261%	382,734

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.Pro366Ser
Coding: c.1096C>T
MANE Select: NM_001379500
dbSNP: rs377028409
Type: single nucleotide variant
Location: chr21:45477840 (GRCh38)
Gene constraint: LOEUF 1.001 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.77 · 9 PDB
Residue 781 UniProt numbering: the 'triple-helical region 1 (col1)' 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.Pro366Leu Uncertain significance ★ ⚠ same residue
COL18A1 p.Pro366= Likely benign ★ 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-pro366ser (accessed [today's date]).

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