Is GORAB p.Met1Ile (c.3G>A) pathogenic?

GORAB p.Met1Ile (c.3G>A) is classified Uncertain significance in GORAB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-10). Very rare (popmax 0.0022%, sas).

How common is GORAB p.Met1Ile (c.3G>A) in the general population?

GORAB p.Met1Ile (c.3G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

GORAB p.Met1Ile

c.3G>A · rs1648721199 · VCV2757894

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.346	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Overall
CADD	23.0	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 0.0022% South Asian · 2/91,068 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000248% 4/1,614,082 alleles · very rare exomes 4/1,461,802 · genomes 0/152,280 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,534
European (non-Finnish)	0.000169%	590,005

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.Met1Ile
Coding: c.3G>A
MANE Select: NM_152281
dbSNP: rs1648721199
Type: single nucleotide variant
Location: chr1:170532226 (GRCh38)
Gene constraint: LOEUF 0.802 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.86
Residue 1: the 'disordered' region

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

Similar variants

GORAB p.Met1Val Likely pathogenic ★ same residue
GORAB c.420-2A>T Pathogenic/Likely pathogenic ★★ same type
GORAB p.Arg262Ter Pathogenic/Likely pathogenic ★★ same type
GORAB p.Arg35Ter Pathogenic ★★ same type
GORAB p.Arg40Ter Pathogenic/Likely pathogenic ★★ same type
GORAB p.Gln64Ter Pathogenic ★★ same type
GORAB p.Trp5Ter Pathogenic/Likely pathogenic ★★ same type
GORAB c.-21G>A Uncertain significance ★★ same type

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-met1ile (accessed [today's date]).

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