Is COL28A1 p.Pro680Arg (c.2039C>G) pathogenic?

COL28A1 p.Pro680Arg (c.2039C>G) is classified Uncertain significance in COL28A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-16). AlphaMissense: likely benign (0.1528); Ultra-rare (popmax 0.0172%, amr).

How common is COL28A1 p.Pro680Arg (c.2039C>G) in the general population?

COL28A1 p.Pro680Arg (c.2039C>G) is ultra-rare (popmax 0.0172%, amr) (gnomAD).

What do computational predictors say about COL28A1 p.Pro680Arg (c.2039C>G)?

AlphaMissense predicts likely benign (score 0.1528) — an in-silico prediction, not a clinical call.

COL28A1 p.Pro680Arg

c.2039C>G · VCV3268699

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1528 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0172%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1528	likely benign
REVEL	0.69	pathogenic-leaning
SaProt	LLR -10.11	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 174 kb · p 8.4e-10 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0172% Admixed American · 10/58,082 alleles

Filtering AF 0.00927% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00701%

Overall 0.00069% 10/1,449,998 alleles · ultra-rare

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: COL28A1
Protein: p.Pro680Arg
Coding: c.2039C>G
MANE Select: NM_001037763
Type: single nucleotide variant
Location: chr7:7419913 (GRCh38)
Gene constraint: LOEUF 1.124 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.81
Residue 680: the 'disordered' region

Full COL28A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL28A1 c.1792-2A>G Uncertain significance ★ same type
COL28A1 p.Ala1075Asp Uncertain significance ★ ⚠ same type
COL28A1 p.Ala274Thr Uncertain significance ★ ⚠ same type
COL28A1 p.Ala535Gly Uncertain significance ★ ⚠ same type
COL28A1 p.Ala631Asp Uncertain significance ★ ⚠ same type
COL28A1 p.Ala825Val Uncertain significance ★ ⚠ same type
COL28A1 p.Ala864Ser Uncertain significance ★ ⚠ same type
COL28A1 p.Arg1087Gln Uncertain significance ★ ⚠ 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/col28a1-p-pro680arg (accessed [today's date]).

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