TCF4 p.Ser330=
c.990G>A · rs587784469 · VCV160092
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Pathogenic for Pitt-Hopkins syndrome. Applied ACMG criteria (verbatim):
PM6 PS2_VeryStrong PM2_Supporting PS4_Supporting PP3
Curation rationale (ClinGen, verbatim)
The p.Ser330= variant in TCF4 is absent from gnomAD v4 (PM2_supporting). Splice prediction analysis using multiple computational tools suggests an impact to splicing (PP3). The p.Ser330= variant has been observed in at least 2 individuals with intellectual disability/autism (PMIDs: 29695756, 25693842) (PS4_supporting). The p.Ser330= variant in TCF4 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with intellectual disability (PMID: 25693842, internal database -Invitae) (PM6). The p.Ser330= variant in TCF4 has been reported as a de novo occurrence (biological parentage confirmed) in at least 3 individuals with intellectual disability/autism (PMIDs: 29695756, 29158550, 31785789, 1981491, 33767182, internal database - Invitae) (PS2_very strong). In summary, the p.Ser330= variant in TCF4 is classified as pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM2_supporting, PP3, PS4_supporting, PM6, PS2_very strong).
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/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.63 | donor loss · deltas |
|---|---|---|
| Pangolin | Δ0.69 | loss · gain 0.09 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 5.9 | GERP 2.6, phastCons 1 |
| Overall | ||
| CADD | 23.6 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- TCF4
- Protein
- p.Ser330=
- Coding
- c.990G>A
- MANE Select
- NM_001083962
- dbSNP
- rs587784469
- Type
- single nucleotide variant
- Location
- chr18:55261466 (GRCh38)
- Gene constraint
- LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 52.08 · 5 PDB
Similar variants
- TCF4 p.Ser330Ter Likely pathogenic ★ same residue
- TCF4 p.Ser330Ala Uncertain significance ★ ⚠ same residue
- TCF4 p.Ser330Leu 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
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-ser330 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown