Is GORAB p.Arg40Ter (c.118C>T) pathogenic?

GORAB p.Arg40Ter (c.118C>T) is classified Pathogenic/Likely pathogenic in GORAB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-12). Very rare (popmax 0.00445%, eas); Associated with geroderma osteodysplasticum.

What condition is associated with GORAB p.Arg40Ter (c.118C>T)?

GORAB p.Arg40Ter (c.118C>T) is associated with geroderma osteodysplasticum (ClinVar).

How common is GORAB p.Arg40Ter (c.118C>T) in the general population?

GORAB p.Arg40Ter (c.118C>T) is very rare (popmax 0.00445%, eas) (gnomAD).

GORAB p.Arg40Ter

c.118C>T · rs369967804 · VCV632088

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Conditions

geroderma osteodysplasticum

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 5
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.63, phastCons 1
Overall
CADD	36.0	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 0.00445% East Asian · 2/44,900 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000805% 13/1,613,992 alleles · very rare exomes 11/1,461,794 · genomes 2/152,198 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,450
African / African-American	0.00267%	37,464
European (non-Finnish)	0.000763%	131,111

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.Arg40Ter
Coding: c.118C>T
MANE Select: NM_152281
dbSNP: rs369967804
Type: single nucleotide variant
Location: chr1:170539266 (GRCh38)
Gene constraint: LOEUF 0.802 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.86
Residue 40: 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.Arg40Gln Uncertain significance ★ same residue
GORAB p.Arg40= Likely benign ★ same residue
GORAB p.Arg262Ter Pathogenic/Likely pathogenic ★★ same condition
GORAB p.Arg35Ter 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-arg40ter (accessed [today's date]).

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