TCF4 p.Ser371=
c.1113G>A · rs148308964 · VCV436960
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Benign for Pitt-Hopkins syndrome. Applied ACMG criteria (verbatim):
BP7 BA1
Curation rationale (ClinGen, verbatim)
The highest population minor allele frequency of the p.Ser371= variant in TCF4 in gnomAD v4.1 is 0.0006424 in the Ashkenazi Jewish population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.000083) for BA1, and therefore meets this criterion (BA1). The silent p.Ser371= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). The p.Ser371= variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the p.Ser371= variant in TCF4 is classified as Benign based on the ACMG/AMP criteria (BA1, BP7). (TCF4 Specifications v.5.0; curation approved on 01/28/2026)
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 | <0.2 | all four deltas below 0.2 · C>G here scores Δ0.28 · evaluated, not missing |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -0.76 | GERP -5.6, phastCons 0.021 |
| Overall | ||
| CADD | 10.14 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Ashkenazi Jewishnot grpmax-eligible | 0.0642% | 1,557 |
| East Asiangrpmax | 0.0267% | 3,740 |
| Remaining individualsnot grpmax-eligible | 0.00961% | 10,410 |
| South Asian | 0.0022% | 45,533 |
| Admixed American | 0.00167% | 59,976 |
| European (non-Finnish) | 0.00153% | 65,540 |
Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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.Ser371=
- Coding
- c.1113G>A
- MANE Select
- NM_001083962
- dbSNP
- rs148308964
- Type
- single nucleotide variant
- Location
- chr18:55257348 (GRCh38)
- Gene constraint
- LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 52.08 · 5 PDB
- Residue 371
- the 'disordered' region
Similar variants
- TCF4 p.Ser371Leu Uncertain significance ★ ⚠ same residue
- 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
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-ser371 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown