Is COL7A1 p.Pro1663Thr (c.4987C>A) pathogenic?

COL7A1 p.Pro1663Thr (c.4987C>A) is classified Uncertain significance in COL7A1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-12-16). AlphaMissense: likely benign (0.0835); Ultra-rare (popmax 0.0318%, sas); Associated with recessive dystrophic epidermolysis bullosa.

What condition is associated with COL7A1 p.Pro1663Thr (c.4987C>A)?

COL7A1 p.Pro1663Thr (c.4987C>A) is associated with recessive dystrophic epidermolysis bullosa, transient bullous dermolysis of the newborn, generalized dominant dystrophic epidermolysis bullosa (ClinVar).

How common is COL7A1 p.Pro1663Thr (c.4987C>A) in the general population?

COL7A1 p.Pro1663Thr (c.4987C>A) is ultra-rare (popmax 0.0318%, sas) (gnomAD).

What do computational predictors say about COL7A1 p.Pro1663Thr (c.4987C>A)?

AlphaMissense predicts likely benign (score 0.0835) — an in-silico prediction, not a clinical call.

COL7A1 p.Pro1663Thr

Q: How is Autosomal recessive generalized dystrophic epidermolysis bullosa, severe form inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.4987C>A · rs149342284 · VCV991830

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0835 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0318%, sas)

Conditions

recessive dystrophic epidermolysis bullosa

Computational evidence

Protein change
AlphaMissense	0.0835	likely benign
REVEL	0.468	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 22 kb · p 7.2e-17 · regional, not allelic
Overall
CADD	24.3	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 0.0318% South Asian · 29/91,076 alleles

Filtering AF 0.026% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0251%

Overall 0.0235% 379/1,613,642 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0318%	3,141
European (non-Finnish)	0.0286%	3,501
Middle Eastern	0.0164%	6,082
Remaining individualsnot grpmax-eligible	0.008%	12,494
Finnishnot grpmax-eligible	0.00781%	12,800
Admixed American	0.00167%	59,964
African / African-American	0.00134%	74,756

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.Pro1663Thr
Coding: c.4987C>A
MANE Select: NM_000094
dbSNP: rs149342284
Type: single nucleotide variant
Location: chr3:48580646 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI <0.01 (gnomAD)
Residue 1663: the 'disordered' region; the 'triple-helical region' region

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

Disease context

recessive dystrophic epidermolysis bullosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: transient bullous dermolysis of the newborn generalized dominant dystrophic epidermolysis bullosa pretibial dystrophic epidermolysis bullosa epidermolysis bullosa with congenital localized absence of skin and deformity of nails dystrophic epidermolysis bullosa pruriginosa nonsyndromic congenital nail disorder 8

For Autosomal recessive generalized dystrophic epidermolysis bullosa, severe form (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

COL7A1 c.1240+1G>T Likely pathogenic ★★ same condition
COL7A1 c.1637-1G>A Pathogenic/Likely pathogenic ★★ same condition
COL7A1 c.1906+1G>T Likely pathogenic ★★ same condition
COL7A1 c.2171-2A>G Likely pathogenic ★★ same condition
COL7A1 c.2587+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL7A1 c.266+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL7A1 c.266+2T>C Pathogenic/Likely pathogenic ★★ same condition
COL7A1 c.2993-2A>G Likely pathogenic ★★ 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-pro1663thr (accessed [today's date]).

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