Is COL18A1 p.Ser320Pro (c.958T>C) pathogenic?

COL18A1 p.Ser320Pro (c.958T>C) is classified Uncertain significance in COL18A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). AlphaMissense: likely benign (0.0958); Very rare (popmax 0.00667%, amr); Associated with Inborn genetic diseases.

What condition is associated with COL18A1 p.Ser320Pro (c.958T>C)?

COL18A1 p.Ser320Pro (c.958T>C) is associated with Inborn genetic diseases (ClinVar).

How common is COL18A1 p.Ser320Pro (c.958T>C) in the general population?

COL18A1 p.Ser320Pro (c.958T>C) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about COL18A1 p.Ser320Pro (c.958T>C)?

AlphaMissense predicts likely benign (score 0.0958) — an in-silico prediction, not a clinical call.

COL18A1 p.Ser320Pro

c.958T>C · VCV4005062

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0958 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0958	likely benign
REVEL	0.263	benign-leaning
SaProt	LLR -6.30	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 -1.5	GERP -2.3
Regional constraint	o/e 1.10	unconstrained · MANE · 107 kb · p 4.9e-06 · regional, not allelic
Overall
CADD	4.39	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 S735P vs ClinVar S320P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,936 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000248% 4/1,613,100 alleles · very rare exomes 2/1,460,928 · genomes 2/152,172 · 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.Ser320Pro
Coding: c.958T>C
MANE Select: NM_001379500
Type: single nucleotide variant
Location: chr21:45477440 (GRCh38)
Gene constraint: LOEUF 1.001 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.77 · 9 PDB
Residue 735 UniProt numbering: the 'disordered' region; the 'nonhelical region 1 (nc1)' 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.Ser320= 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
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-ser320pro (accessed [today's date]).

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