Is COL7A1 p.Pro1337Ala (c.4009C>G) pathogenic?

COL7A1 p.Pro1337Ala (c.4009C>G) is classified Uncertain significance in COL7A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-17). AlphaMissense: likely benign (0.059); Ultra-rare (popmax 0.0423%, eas); Associated with Inborn genetic diseases.

What condition is associated with COL7A1 p.Pro1337Ala (c.4009C>G)?

COL7A1 p.Pro1337Ala (c.4009C>G) is associated with Inborn genetic diseases (ClinVar).

How common is COL7A1 p.Pro1337Ala (c.4009C>G) in the general population?

COL7A1 p.Pro1337Ala (c.4009C>G) is ultra-rare (popmax 0.0423%, eas) (gnomAD).

What do computational predictors say about COL7A1 p.Pro1337Ala (c.4009C>G)?

AlphaMissense predicts likely benign (score 0.059) — an in-silico prediction, not a clinical call.

COL7A1 p.Pro1337Ala

c.4009C>G · rs774162615 · VCV2148189

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.059 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0423%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.059	likely benign
REVEL	0.229	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -1.7, phastCons 0.019
Regional constraint	o/e 0.83	unconstrained · MANE · 22 kb · p 7.2e-17 · regional, not allelic
Overall
CADD	12.57	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0423% East Asian · 19/44,900 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.023%

Overall 0.00124% 20/1,613,900 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0423%	2,363
Admixed American	0.00167%	59,998

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.Pro1337Ala
Coding: c.4009C>G
MANE Select: NM_000094
dbSNP: rs774162615
Type: single nucleotide variant
Location: chr3:48584912 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI <0.01 (gnomAD)
Residue 1337: the 'disordered' region; the 'triple-helical region' region; the 'interrupted collagenous region' 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.Pro1337Leu Uncertain significance ★★ ⚠ same residue
COL7A1 p.Pro1337= Pathogenic/Likely pathogenic ★★ same residue
COL7A1 p.Pro1337Ser Uncertain significance ⚠ same residue
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

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-pro1337ala (accessed [today's date]).

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