LARGE1 p.Pro668=
c.2004G>A · rs368231947 · VCV386898
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 4 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0719%, afr)
Conditions
1
muscular dystrophy-dystroglycanopathy type B6
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 -3.2 | GERP -4 |
| Overall | ||
| CADD | 0.563 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0719%
African / African-American · 54/75,072 alleles
Filtering AF
0.0566%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.051%
Overall
0.00929%
150/1,614,254 alleles · ultra-rare
exomes 127/1,461,888 · genomes 23/152,366 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.0719% | 1,390 |
| Middle Eastern | 0.066% | 1,516 |
| Remaining individualsnot grpmax-eligible | 0.0272% | 3,677 |
| Finnishnot grpmax-eligible | 0.0156% | 6,405 |
| Admixed American | 0.00666% | 15,009 |
| European (non-Finnish) | 0.00492% | 20,346 |
| South Asian | 0.00329% | 30,363 |
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
- LARGE1
- Protein
- p.Pro668=
- Coding
- c.2004G>A
- MANE Select
- NM_133642
- dbSNP
- rs368231947
- Type
- single nucleotide variant
- Location
- chr22:33277129 (GRCh38)
- Gene constraint
- LOEUF 0.606 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 86.15 · 4 PDB
- Residue 668
- the 'glucuronyltransferase activity' region; an α-helix
Similar variants
- LARGE1 p.Arg95Ter Pathogenic ★★ same condition
- LARGE1 p.Glu509Lys Pathogenic/Likely pathogenic ★★ same condition
- LARGE1 c.*155C>T Uncertain significance ★★ same condition
- LARGE1 p.Ala149Ser Uncertain significance ★★ ⚠ same condition
- LARGE1 p.Ala252Val Uncertain significance ★★ ⚠ same condition
- LARGE1 p.Ala478Thr Uncertain significance ★★ ⚠ same condition
- LARGE1 p.Ala635Thr Uncertain significance ★★ ⚠ same condition
- LARGE1 p.Ala752Gly 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/large1-p-pro668 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown