Is COL18A1 p.Pro708Ser (c.2122C>T) pathogenic?

COL18A1 p.Pro708Ser (c.2122C>T) is classified Uncertain significance in COL18A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-31). AlphaMissense: likely benign (0.1396); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with COL18A1 p.Pro708Ser (c.2122C>T)?

COL18A1 p.Pro708Ser (c.2122C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL18A1 p.Pro708Ser (c.2122C>T) in the general population?

COL18A1 p.Pro708Ser (c.2122C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COL18A1 p.Pro708Ser (c.2122C>T)?

AlphaMissense predicts likely benign (score 0.1396) — an in-silico prediction, not a clinical call.

COL18A1 p.Pro708Ser

c.2122C>T · VCV3268585

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1396 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1396	likely benign
REVEL	0.463	indeterminate
SaProt	LLR -11.56	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 0.22, phastCons 0.13
Regional constraint	o/e 1.10	unconstrained · MANE · 107 kb · p 4.9e-06 · regional, not allelic
Overall
CADD	18.6	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 P1123S vs ClinVar P708S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COL18A1
Protein: p.Pro708Ser
Coding: c.2122C>T
MANE Select: NM_001379500
Type: single nucleotide variant
Location: chr21:45491279 (GRCh38)
Gene constraint: LOEUF 1.001 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.77 · 9 PDB
Residue 1123 UniProt numbering: the 'triple-helical region 4 (col4)' 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.Pro708Thr Uncertain significance ★ ⚠ same residue
COL18A1 p.Pro708= 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-pro708ser (accessed [today's date]).

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