Is COL18A1 p.Pro758Ser (c.2272C>T) pathogenic?

COL18A1 p.Pro758Ser (c.2272C>T) is classified Uncertain significance in COL18A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-04). AlphaMissense: likely benign (0.1034); Very rare (popmax 0.000608%, nfe).

How common is COL18A1 p.Pro758Ser (c.2272C>T) in the general population?

COL18A1 p.Pro758Ser (c.2272C>T) is very rare (popmax 0.000608%, nfe) (gnomAD).

What do computational predictors say about COL18A1 p.Pro758Ser (c.2272C>T)?

AlphaMissense predicts likely benign (score 0.1034) — an in-silico prediction, not a clinical call.

COL18A1 p.Pro758Ser

c.2272C>T · rs2145993816 · VCV1525261

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1034 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000608%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1034	likely benign
REVEL	0.29	benign-leaning
SaProt	LLR -7.75	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 2.2	GERP 0.24, phastCons 0.97
Regional constraint	o/e 1.10	unconstrained · MANE · 107 kb · p 4.9e-06 · regional, not allelic
Overall
CADD	20.3	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 P1173S vs ClinVar P758S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000608% European (non-Finnish) · 7/1,151,010 alleles

Filtering AF 0.000253% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000163%

Overall 0.000449% 7/1,558,356 alleles · very rare exomes 7/1,406,068 · genomes 0/152,288 · 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.Pro758Ser
Coding: c.2272C>T
MANE Select: NM_001379500
dbSNP: rs2145993816
Type: single nucleotide variant
Location: chr21:45493220 (GRCh38)
Gene constraint: LOEUF 1.001 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.77 · 9 PDB
Residue 1173 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.Pro758= Likely benign ★ same residue
COL18A1 p.Pro758fs Pathogenic ★ 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-pro758ser (accessed [today's date]).

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