CTLA4 p.Ser172=
c.516G>A · rs375949600 · VCV1143236
ClinGen expert panel — Antibody Deficiencies VCEP
Benign for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency. Applied ACMG criteria (verbatim):
BA1
Curation rationale (ClinGen, verbatim)
NM_005214.5(CTLA4):c.516G>A (p.Ser172=) is a synonymous variant in exon 2 but has an intermediate prediction of impact at splicing sites, so BP7 is not met. The splicing impact predictor SpliceAI gives a delta score of 0.10 for donor loss, which is higher than the ClinGen Antibody Deficiencies VCEP recommended threshold of <0.1 and does not meet the BP4 code. This variant is present in gnomAD v4.1.0 at a GrpMax allele frequency of 0.0005198, with 50 alleles / 74,906 total alleles in the African / African-American population, which is higher than the ClinGen Antibody Deficiencies VCEP BA1 threshold of >0.0000111 (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Antibody Deficiencies VCEP: BA1. (VCEP specifications version 1.0.0; date of approval 09/18/2025).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
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 | GERP -3.1 |
| Overall | ||
| CADD | 3.984 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.0668% | 1,498 |
| Remaining individualsnot grpmax-eligible | 0.008% | 12,497 |
| Admixed American | 0.00333% | 29,998 |
| East Asian | 0.00223% | 44,898 |
| South Asian | 0.0011% | 91,082 |
| European (non-Finnish) | 0.000678% | 147,502 |
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
- CTLA4
- Protein
- p.Ser172=
- Coding
- c.516G>A
- MANE Select
- NM_005214
- dbSNP
- rs375949600
- Type
- single nucleotide variant
- Location
- chr2:203871436 (GRCh38)
- Gene constraint
- LOEUF 0.211 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 79.67 · 22 PDB
Disease context
autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency (Orphanet):
- Inheritance
- Autosomal dominant
- Onset
- Adolescent, Adult, Childhood
Similar variants
- CTLA4 p.Ser172Leu Benign ★★★ same residue
- CTLA4 p.Arg51Ter Pathogenic ★★★ same condition
- CTLA4 p.Arg75Trp Pathogenic ★★★ ⚠ same condition
- CTLA4 p.Asp153Asn Pathogenic ★★★ ⚠ same condition
- CTLA4 p.Cys35Ter Pathogenic ★★★ same condition
- CTLA4 p.Pro136Ala Likely pathogenic ★★★ same condition
- CTLA4 p.Pro136Leu Likely pathogenic ★★★ same condition
- CTLA4 p.Pro136Ser 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/ctla4-p-ser172 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown