Is COL7A1 p.Pro227Arg (c.680C>G) pathogenic?

COL7A1 p.Pro227Arg (c.680C>G) is classified Uncertain significance in COL7A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-26). AlphaMissense: likely benign (0.0993); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with COL7A1 p.Pro227Arg (c.680C>G)?

COL7A1 p.Pro227Arg (c.680C>G) is associated with Inborn genetic diseases (ClinVar).

How common is COL7A1 p.Pro227Arg (c.680C>G) in the general population?

COL7A1 p.Pro227Arg (c.680C>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about COL7A1 p.Pro227Arg (c.680C>G)?

AlphaMissense predicts likely benign (score 0.0993) — an in-silico prediction, not a clinical call.

COL7A1 p.Pro227Arg

c.680C>G · rs1450480489 · VCV1491769

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0993 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0993	likely benign
REVEL	0.421	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 6,279 bp · p 1.1e-07 · regional, not allelic
Overall
CADD	19.84	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 0.000424% European (non-Finnish) · 5/1,180,028 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,022 alleles · very 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: COL7A1
Protein: p.Pro227Arg
Coding: c.680C>G
MANE Select: NM_000094
dbSNP: rs1450480489
Type: single nucleotide variant
Location: chr3:48593104 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI <0.01 (gnomAD)
Residue 227: the 'nonhelical region (nc1)' region

Full COL7A1 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

COL7A1 p.Ala1282Thr Uncertain significance ★★ ⚠ same condition
COL7A1 p.Ala2258Thr Uncertain significance ★★ ⚠ same condition
COL7A1 p.Ala2328Gly Uncertain significance ★★ same condition
COL7A1 p.Ala2513Val Uncertain significance ★★ ⚠ same condition
COL7A1 p.Ala2592Glu Uncertain significance ★★ same condition
COL7A1 p.Ala36Thr Uncertain significance ★★ same condition
COL7A1 p.Ala74Thr Uncertain significance ★★ ⚠ same condition
COL7A1 p.Ala74Val 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/col7a1-p-pro227arg (accessed [today's date]).

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