Is COL18A1 p.Ser460Phe (c.1379C>T) pathogenic?

COL18A1 p.Ser460Phe (c.1379C>T) is classified Uncertain significance in COL18A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-13). AlphaMissense: likely benign (0.1909); Ultra-rare (popmax 0.0175%, afr); Associated with Inborn genetic diseases.

What condition is associated with COL18A1 p.Ser460Phe (c.1379C>T)?

COL18A1 p.Ser460Phe (c.1379C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL18A1 p.Ser460Phe (c.1379C>T) in the general population?

COL18A1 p.Ser460Phe (c.1379C>T) is ultra-rare (popmax 0.0175%, afr) (gnomAD).

What do computational predictors say about COL18A1 p.Ser460Phe (c.1379C>T)?

AlphaMissense predicts likely benign (score 0.1909) — an in-silico prediction, not a clinical call.

COL18A1 p.Ser460Phe

c.1379C>T · rs750465152 · VCV1369373

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1909 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1909	likely benign
REVEL	0.459	indeterminate
SaProt	LLR -8.92	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.92, phastCons 0.73
Regional constraint	o/e 1.10	unconstrained · MANE · 107 kb · p 4.9e-06 · regional, not allelic
Overall
CADD	24.2	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 S875F vs ClinVar S460F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0175% African / African-American · 13/74,390 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00818%

Overall 0.000944% 15/1,588,812 alleles · ultra-rare exomes 6/1,436,590 · genomes 9/152,222 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0175%	5,722
European (non-Finnish)	0.000173%	578,932

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.Ser460Phe
Coding: c.1379C>T
MANE Select: NM_001379500
dbSNP: rs750465152
Type: single nucleotide variant
Location: chr21:45480137 (GRCh38)
Gene constraint: LOEUF 1.001 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.77 · 9 PDB
Residue 875 UniProt numbering: the 'triple-helical region 2 (col2)' 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.Ser460Tyr 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-ser460phe (accessed [today's date]).

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