TCF4 p.Val168=
c.504A>G · rs370160994 · VCV139404
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Benign for Pitt-Hopkins syndrome. Applied ACMG criteria (verbatim):
BS2_Supporting BA1
Curation rationale (ClinGen, verbatim)
The allele frequency of the p.Val168= variant in TCF4 is 0.057% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Val168= variant is observed in 1 unaffected individual (Baylor Genetics internal database) (BS2_supporting). In summary, p.Val168= variant in TCF4 is classified as benign based on the ACMG/AMP criteria (BA1, BS2_supporting).
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 -0.15 | GERP -5.2, phastCons 0.54 |
| Overall | ||
| CADD | 3.019 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.0609% | 1,643 |
| Remaining individualsnot grpmax-eligible | 0.024% | 4,163 |
| African / African-American | 0.0214% | 4,682 |
| Admixed American | 0.0117% | 8,566 |
| South Asian | 0.011% | 9,108 |
| Finnishnot grpmax-eligible | 0.00781% | 12,799 |
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.Val168=
- Coding
- c.504A>G
- MANE Select
- NM_001083962
- dbSNP
- rs370160994
- Type
- single nucleotide variant
- Location
- chr18:55350404 (GRCh38)
- Gene constraint
- LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 52.08 · 5 PDB
- Residue 168
- 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-val168 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown