Is GORAB p.Arg28Cys (c.82C>T) pathogenic?

GORAB p.Arg28Cys (c.82C>T) is classified Uncertain significance in GORAB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-04-11). Ultra-rare (popmax 0.0117%, amr); Associated with geroderma osteodysplasticum.

What condition is associated with GORAB p.Arg28Cys (c.82C>T)?

GORAB p.Arg28Cys (c.82C>T) is associated with geroderma osteodysplasticum (ClinVar).

How common is GORAB p.Arg28Cys (c.82C>T) in the general population?

GORAB p.Arg28Cys (c.82C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

GORAB p.Arg28Cys

c.82C>T · rs761243601 · VCV876748

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Conditions

geroderma osteodysplasticum

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.165	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.69, phastCons 0.99
Regional constraint	o/e 1.01	unconstrained · MANE · 20 kb · p 0.84 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/59,980 alleles

Filtering AF 0.00544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00143% 23/1,613,992 alleles · ultra-rare exomes 22/1,461,802 · genomes 1/152,190 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,569
South Asian	0.0022%	45,544
Remaining individualsnot grpmax-eligible	0.0016%	62,490
Finnishnot grpmax-eligible	0.00156%	64,028
African / African-American	0.00133%	74,910
European (non-Finnish)	0.000932%	107,274

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.Arg28Cys
Coding: c.82C>T
MANE Select: NM_152281
dbSNP: rs761243601
Type: single nucleotide variant
Location: chr1:170539230 (GRCh38)
Gene constraint: LOEUF 0.802 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.86
Residue 28: 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.Arg28His Conflicting classifications of pathogenicity ★ same residue
GORAB p.Arg262Ter Pathogenic/Likely pathogenic ★★ same condition
GORAB p.Arg35Ter Pathogenic ★★ same condition
GORAB p.Arg40Ter Pathogenic/Likely pathogenic ★★ same condition
GORAB p.Gln64Ter Pathogenic ★★ same condition
GORAB c.-21G>A Uncertain significance ★★ same condition
GORAB c.-28C>G Uncertain significance ★★ same condition
GORAB c.-53C>A 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/gorab-p-arg28cys (accessed [today's date]).

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