Is COL28A1 p.Pro403Arg (c.1208C>G) pathogenic?

COL28A1 p.Pro403Arg (c.1208C>G) is classified Uncertain significance in COL28A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-01). AlphaMissense: likely benign (0.1699); Very rare (popmax 0.00143%, afr).

How common is COL28A1 p.Pro403Arg (c.1208C>G) in the general population?

COL28A1 p.Pro403Arg (c.1208C>G) is very rare (popmax 0.00143%, afr) (gnomAD).

What do computational predictors say about COL28A1 p.Pro403Arg (c.1208C>G)?

AlphaMissense predicts likely benign (score 0.1699) — an in-silico prediction, not a clinical call.

COL28A1 p.Pro403Arg

c.1208C>G · rs1788958506 · VCV2657316

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1699 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00143%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1699	likely benign
REVEL	0.751	pathogenic-leaning
SaProt	LLR -8.43	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.8, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 174 kb · p 8.4e-10 · regional, not allelic
Overall
CADD	25.2	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 0.00143% African / African-American · 1/70,106 alleles

Overall 0.000167% 2/1,198,030 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00143%	70,106
European (non-Finnish)	0.000107%	938,782

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.Pro403Arg
Coding: c.1208C>G
MANE Select: NM_001037763
dbSNP: rs1788958506
Type: single nucleotide variant
Location: chr7:7477137 (GRCh38)
Gene constraint: LOEUF 1.124 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.81
Residue 403: the 'disordered' region; the collagen-like 3 domain

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

Similar variants

COL28A1 p.Pro403Ser Uncertain significance ★ ⚠ same residue
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

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-pro403arg (accessed [today's date]).

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