FREM2 p.Arg1523=
c.4569T>C · rs146585542 · VCV1192243
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0164%, mid)
Conditions
2
isolated cryptophthalmia
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 -2.3 | GERP -5.4 |
| Overall | ||
| CADD | 1.584 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0164%
Middle Eastern · 1/6,084 alleles
Filtering AF
0.00258%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00233%
Overall
0.00285%
46/1,614,074 alleles · ultra-rare
exomes 40/1,461,852 · genomes 6/152,222 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0164% | 6,084 |
| European (non-Finnish) | 0.00347% | 28,782 |
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,244 |
| African / African-American | 0.00267% | 37,474 |
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
- FREM2
- Protein
- p.Arg1523=
- Coding
- c.4569T>C
- MANE Select
- NM_207361
- dbSNP
- rs146585542
- Type
- single nucleotide variant
- Location
- chr13:38691913 (GRCh38)
- Gene constraint
- LOEUF 0.588 · pLI <0.01 (gnomAD)
- Residue 1523
- a UniProt-annotated variant site (in cryptop)
Similar variants
- FREM2 p.Arg1523Cys Uncertain significance ★★ same residue
- FREM2 p.Arg1523His Uncertain significance ★ same residue
- FREM2 p.Arg1355Ter Pathogenic/Likely pathogenic ★★ same condition
- FREM2 p.Arg638Ter Likely pathogenic ★★ same condition
- FREM2 p.Arg736Ter Pathogenic ★★ same condition
- FREM2 p.Arg809Ter Pathogenic ★★ same condition
- FREM2 p.Gln1051Ter Pathogenic/Likely pathogenic ★★ same condition
- FREM2 p.Gln717Ter Likely pathogenic ★★ 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/frem2-p-arg1523 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown