Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 8 submitters
gnomAD v4.1
Common
common (popmax 17.8%, amr) — too common for a highly-penetrant pathogenic allele
Conditions
1
autoimmune lymphoproliferative syndrome type 1
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 -0.046 | GERP -0.95 |
| Overall | ||
| CADD | 1.604 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
17.8%
Admixed American · 10,668/59,944 alleles
Filtering AF
17.5%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 17.4%
Overall
4.9%
79,148/1,613,964 alleles · common
exomes 72,982/1,461,692 · genomes 6,166/152,272 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 17.8% | 6 |
| South Asian | 6.14% | 16 |
| European (non-Finnish) | 4.67% | 21 |
| Remaining individualsnot grpmax-eligible | 4.44% | 23 |
| Middle Eastern | 4.07% | 25 |
| Finnishnot grpmax-eligible | 3.66% | 27 |
| East Asian | 2.35% | 43 |
| Ashkenazi Jewishnot grpmax-eligible | 2.3% | 43 |
| Amishnot grpmax-eligible | 1.65% | 61 |
| African / African-American | 0.969% | 103 |
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
- FAS
- Protein
- p.Thr74=
- Coding
- c.222A>G
- MANE Select
- NM_000043
- dbSNP
- rs2229521
- Type
- single nucleotide variant
- Location
- chr10:89007725 (GRCh38)
- Gene constraint
- LOEUF 0.372 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
- Structure
- AlphaFold pLDDT 78.21 · 7 PDB
Disease context
autoimmune lymphoproliferative syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor Autoimmune lymphoproliferative syndrome (Orphanet):
- Inheritance
- Autosomal dominant, Autosomal recessive
- Onset
- All ages
Similar variants
- FAS c.651+1G>A Pathogenic/Likely pathogenic ★★ same condition
- FAS c.651+2T>C Pathogenic ★★ same condition
- FAS p.Arg250Gln Pathogenic/Likely pathogenic ★★ same condition
- FAS p.Arg250Gly Likely pathogenic ★★ same condition
- FAS p.Arg250Ter Pathogenic/Likely pathogenic ★★ same condition
- FAS p.Asp260Asn Pathogenic ★★ ⚠ same condition
- FAS p.Cys135Tyr Likely pathogenic ★★ same condition
- FAS p.Glu272Lys Pathogenic/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/fas-p-thr74 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown