TCF4 p.Ser229=
c.687C>A · rs200800656 · VCV327305
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Likely Benign for Pitt-Hopkins syndrome. Applied ACMG criteria (verbatim):
BS1 BP7
Curation rationale (ClinGen, verbatim)
The allele frequency of the p.Ser229= variant in TCF4 is 0.027% in East Asian sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The silent p.Ser229= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Ser229= variant in TCF4 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP7).
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 8.7 | GERP 1.1, phastCons 1 |
| Overall | ||
| CADD | 12.02 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.314% | 318 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,496 |
| European (non-Finnish) | 0.000254% | 393,260 |
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
- TCF4
- Protein
- p.Ser229=
- Coding
- c.687C>A
- MANE Select
- NM_001083962
- dbSNP
- rs200800656
- Type
- single nucleotide variant
- Location
- chr18:55275721 (GRCh38)
- Gene constraint
- LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 52.08 · 5 PDB
- Residue 229
- the 'disordered' region
Similar variants
- TCF4 p.Arg576Gln Pathogenic ★★★ same condition
- TCF4 p.Arg578His Pathogenic ★★★ same condition
- TCF4 p.Arg580Gln Pathogenic ★★★ same condition
- TCF4 p.Arg580Trp Pathogenic ★★★ same condition
- TCF4 p.Arg582Cys Likely pathogenic ★★★ same condition
- TCF4 p.Gly496Cys Likely pathogenic ★★★ ⚠ same condition
- TCF4 p.Gly592Ser Likely pathogenic ★★★ same condition
- TCF4 p.Leu609Pro 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/tcf4-p-ser229 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown