Is EXPH5 p.Pro1929fs (c.5786del) pathogenic?

EXPH5 p.Pro1929fs (c.5786del) is classified Pathogenic in EXPH5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-09). Ultra-rare (popmax 0.0165%, mid); Associated with epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive.

How common is EXPH5 p.Pro1929fs (c.5786del) in the general population?

EXPH5 p.Pro1929fs (c.5786del) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

EXPH5 p.Pro1929fs

Q: What condition is associated with EXPH5 p.Pro1929fs (c.5786del)?

EXPH5 p.Pro1929fs (c.5786del) is associated with epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive (ClinVar).

Q: How is Epidermolysis bullosa simplex due to exophilin 5 deficiency inherited?

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

c.5786del · rs749309384 · VCV265125

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (6 of 6) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.2	GERP -0.28, phastCons 0.009
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,044 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00242% 39/1,609,238 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,044
East Asian	0.00891%	11,218
Admixed American	0.0068%	14,701
European (non-Finnish)	0.00246%	40,643
South Asian	0.00111%	89,986

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: EXPH5
Protein: p.Pro1929fs
Coding: c.5786del
MANE Select: NM_015065
dbSNP: rs749309384
Type: Deletion
Location: chr11:108509721 (GRCh38)
Gene constraint: LOEUF 1.142 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 36.39
Residue 1929: the 'disordered' region

Full EXPH5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Epidermolysis bullosa simplex due to exophilin 5 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

EXPH5 p.Asn314fs Pathogenic/Likely pathogenic ★★ same condition
EXPH5 p.Glu30fs Likely pathogenic ★ same condition
EXPH5 p.Lys1141fs Likely pathogenic ★ same condition
EXPH5 p.Pro1929Thr Uncertain significance ★ ⚠ same residue
EXPH5 p.His848fs Pathogenic same condition
EXPH5 p.Phe466fs Pathogenic same condition
EXPH5 p.Pro966fs Pathogenic same condition
EXPH5 p.Arg19Gly Benign ★★ 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/exph5-p-pro1929fs (accessed [today's date]).

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