Is COL18A1 p.Pro495Ser (c.1483C>T) pathogenic?

COL18A1 p.Pro495Ser (c.1483C>T) is classified Uncertain significance in COL18A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-18). AlphaMissense: ambiguous (0.3934); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with COL18A1 p.Pro495Ser (c.1483C>T)?

COL18A1 p.Pro495Ser (c.1483C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL18A1 p.Pro495Ser (c.1483C>T) in the general population?

COL18A1 p.Pro495Ser (c.1483C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about COL18A1 p.Pro495Ser (c.1483C>T)?

AlphaMissense predicts ambiguous (score 0.3934) — an in-silico prediction, not a clinical call.

COL18A1 p.Pro495Ser

c.1483C>T · rs375739796 · VCV1409678

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3934 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3934	ambiguous
REVEL	0.492	indeterminate
SaProt	LLR -11.02	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.9, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 107 kb · p 4.9e-06 · regional, not allelic
Overall
CADD	22.6	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 P910S vs ClinVar P495S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,902 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00441% 71/1,610,136 alleles · very rare exomes 63/1,458,008 · genomes 8/152,128 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00641%	15,611
African / African-Americangrpmax	0.00534%	18,726
European (non-Finnish)	0.00517%	19,343
Admixed American	0.00167%	59,974
South Asian	0.0011%	91,074

Remaining individuals 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: COL18A1
Protein: p.Pro495Ser
Coding: c.1483C>T
MANE Select: NM_001379500
dbSNP: rs375739796
Type: single nucleotide variant
Location: chr21:45480730 (GRCh38)
Gene constraint: LOEUF 1.001 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.77 · 9 PDB
Residue 910 UniProt numbering: the 'triple-helical region 3 (col3)' 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.Pro495Arg 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
COL18A1 p.Ala519Thr 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-pro495ser (accessed [today's date]).

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