Is GORAB p.Tyr219= (c.657C>T) pathogenic?

GORAB p.Tyr219= (c.657C>T) is classified Benign in GORAB (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-31). Low-frequency (popmax 3%, afr); Associated with geroderma osteodysplasticum.

What condition is associated with GORAB p.Tyr219= (c.657C>T)?

GORAB p.Tyr219= (c.657C>T) is associated with geroderma osteodysplasticum (ClinVar).

How common is GORAB p.Tyr219= (c.657C>T) in the general population?

GORAB p.Tyr219= (c.657C>T) is low-frequency (popmax 3%, afr) (gnomAD).

GORAB p.Tyr219=

c.657C>T · rs76365864 · VCV293659

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3%, afr)

Conditions

geroderma osteodysplasticum

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.12	GERP -4.7, phastCons 0.74
Overall
CADD	8.597	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3% African / African-American · 2,249/74,920 alleles

Filtering AF 2.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.86%

Overall 0.172% 2,765/1,608,462 alleles · low-frequency exomes 1,368/1,456,198 · genomes 1,397/152,264 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3%	33
Admixed American	0.265%	377
Remaining individualsnot grpmax-eligible	0.207%	483
Middle Eastern	0.0992%	1,008
South Asian	0.032%	3,129
European (non-Finnish)	0.0163%	6,122
Finnishnot grpmax-eligible	0.00156%	63,926

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.Tyr219=
Coding: c.657C>T
MANE Select: NM_152281
dbSNP: rs76365864
Type: single nucleotide variant
Location: chr1:170544840 (GRCh38)
Gene constraint: LOEUF 0.802 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.86
Residue 219: the 'necessary for interaction with rchy1' 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.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
GORAB p.Ala220Thr 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-tyr219 (accessed [today's date]).

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