LSS p.Val674=
c.2022C>T · rs774054684 · VCV2894049
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0237%, nfe)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.015 | strongly benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 3.4 | GERP -2.8, phastCons 1 |
| Overall | ||
| CADD | 5.206 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0237%
European (non-Finnish) · 280/1,179,938 alleles
Filtering AF
0.0214%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0205%
Overall
0.0175%
283/1,613,674 alleles · ultra-rare
exomes 279/1,461,472 · genomes 4/152,202 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.0237% | 4,214 |
| Remaining individualsnot grpmax-eligible | 0.0048% | 20,827 |
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
- LSS
- Protein
- p.Val674=
- Coding
- c.2022C>T
- MANE Select
- NM_002340
- dbSNP
- rs774054684
- Type
- single nucleotide variant
- Location
- chr21:46191926 (GRCh38)
- Gene constraint
- LOEUF 1.05 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 98.05 · 2 PDB
- Residue 674
- a UniProt-annotated variant site (in apmr4; loss of protein expression); a UniProt-annotated variant site (in apmr4; uncertain significance); an α-helix
Similar variants
- LSS p.Arg177Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
- LSS p.Asn516Ser Likely pathogenic ★★ ⚠ same type
- LSS p.Trp216Ter Pathogenic ★★ same type
- LSS p.Tyr286Cys Likely pathogenic ★★ ⚠ same type
- LSS p.Ala399Val Uncertain significance ★★ ⚠ same type
- LSS p.Ala73Thr Uncertain significance ★★ ⚠ same type
- LSS p.Arg129Gln Uncertain significance ★★ same type
- LSS p.Arg260His 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/lss-p-val674 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown