Is COL7A1 p.Pro657Arg (c.1970C>G) pathogenic?

COL7A1 p.Pro657Arg (c.1970C>G) is classified Uncertain significance in COL7A1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-14). AlphaMissense: ambiguous (0.3702); Very rare (popmax 0.00401%, afr).

How common is COL7A1 p.Pro657Arg (c.1970C>G) in the general population?

COL7A1 p.Pro657Arg (c.1970C>G) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about COL7A1 p.Pro657Arg (c.1970C>G)?

AlphaMissense predicts ambiguous (score 0.3702) — an in-silico prediction, not a clinical call.

COL7A1 p.Pro657Arg

c.1970C>G · rs369972686 · VCV444601

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3702 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Computational evidence

Protein change
AlphaMissense	0.3702	ambiguous
REVEL	0.501	indeterminate
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 0.84	unconstrained · MANE · 6,279 bp · p 1.1e-07 · regional, not allelic
Overall
CADD	23.0	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 0.00401% African / African-American · 3/74,902 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000805% 13/1,613,938 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,967
Remaining individualsnot grpmax-eligible	0.0032%	31,241
Admixed American	0.00167%	59,984
European (non-Finnish)	0.000593%	168,572

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.Pro657Arg
Coding: c.1970C>G
MANE Select: NM_000094
dbSNP: rs369972686
Type: single nucleotide variant
Location: chr3:48590293 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI <0.01 (gnomAD)
Residue 657: the 'nonhelical region (nc1)' region; the fibronectin type-iii 5 domain

Full COL7A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL7A1 p.Pro657Ser Uncertain significance ★ same residue
COL7A1 c.1240+1G>T Likely pathogenic ★★ same type
COL7A1 c.1637-1G>A Pathogenic/Likely pathogenic ★★ same type
COL7A1 c.1906+1G>T Likely pathogenic ★★ same type
COL7A1 c.2171-2A>G Likely pathogenic ★★ same type
COL7A1 c.2587+1G>A Pathogenic/Likely pathogenic ★★ same type
COL7A1 c.2587+40G>A Pathogenic/Likely pathogenic ★★ same type
COL7A1 c.266+1G>A Pathogenic/Likely pathogenic ★★ 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/col7a1-p-pro657arg (accessed [today's date]).

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