FREM2 p.Val1249=
c.3747C>T · rs773900493 · VCV744713
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0493%, mid)
Conditions
2
isolated cryptophthalmia
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -10 | GERP -5.3 |
| Overall | ||
| CADD | 0.15 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0493%
Middle Eastern · 3/6,084 alleles
Filtering AF
0.0134%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00715%
Overall
0.00186%
30/1,613,836 alleles · ultra-rare
exomes 27/1,461,868 · genomes 3/151,968 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0493% | 2,028 |
| Remaining individualsnot grpmax-eligible | 0.008% | 12,498 |
| African / African-American | 0.00535% | 18,702 |
| East Asian | 0.00446% | 22,442 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00338% | 29,606 |
| Admixed American | 0.00167% | 59,984 |
| European (non-Finnish) | 0.00119% | 84,286 |
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.Val1249=
- Coding
- c.3747C>T
- MANE Select
- NM_207361
- dbSNP
- rs773900493
- Type
- single nucleotide variant
- Location
- chr13:38691091 (GRCh38)
- Gene constraint
- LOEUF 0.588 · pLI <0.01 (gnomAD)
- Residue 1249
- a UniProt-annotated variant site (in cryptop)
Similar variants
- FREM2 p.Val1249Phe 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
- FREM2 p.Ala1659Thr 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/frem2-p-val1249 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown