Is GORAB p.Pro86fs (c.257del) pathogenic?

GORAB p.Pro86fs (c.257del) is classified Pathogenic/Likely pathogenic in GORAB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-02). Very rare (popmax 0.000763%, nfe); Associated with geroderma osteodysplasticum.

What condition is associated with GORAB p.Pro86fs (c.257del)?

GORAB p.Pro86fs (c.257del) is associated with geroderma osteodysplasticum (ClinVar).

How common is GORAB p.Pro86fs (c.257del) in the general population?

GORAB p.Pro86fs (c.257del) is very rare (popmax 0.000763%, nfe) (gnomAD).

GORAB p.Pro86fs

c.257del · rs747376663 · VCV2734028

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Conditions

geroderma osteodysplasticum

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 5
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.44	GERP 1.6
Overall
CADD	17.66	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 0.000763% European (non-Finnish) · 9/1,180,004 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000991% 16/1,613,970 alleles · very rare exomes 15/1,461,848 · genomes 1/152,122 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,498
Finnishnot grpmax-eligible	0.00312%	32,013
European (non-Finnish)grpmax	0.000763%	131,112

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: GORAB
Protein: p.Pro86fs
Coding: c.257del
MANE Select: NM_152281
dbSNP: rs747376663
Type: Deletion
Location: chr1:170539404 (GRCh38)
Gene constraint: LOEUF 0.802 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.86
Residue 86: the 'disordered' region

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

Disease context

geroderma osteodysplasticum — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GORAB p.Ala2fs Pathogenic/Likely pathogenic ★★ same condition
GORAB p.Lys137fs Pathogenic/Likely pathogenic ★★ same condition
GORAB p.Pro86Leu Uncertain significance ★★ same residue
GORAB p.Ser335fs Uncertain significance ★★ same condition
GORAB p.Gly96fs Likely pathogenic ★ same condition
GORAB p.Pro86_Ser87delinsArgGly Uncertain significance ★ same residue
GORAB p.Pro86= Likely benign ★ same residue
GORAB p.Arg262Ter Pathogenic/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/gorab-p-pro86fs (accessed [today's date]).

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