TCF4 p.Val581Phe
c.1741G>T · rs587784460 · VCV160079
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Likely Pathogenic for Pitt-Hopkins syndrome. Applied ACMG criteria (verbatim):
PM6 PM2_Supporting PS4_Supporting PM1 PP3
Curation rationale (ClinGen, verbatim)
The p.Val581Phe variant in TCF4 is located in the basic Helix-Loop-Helix domain (bHLH) (PMID 17436254, 22045651) (PM1). This variant is absent from gnomAD (PM2_supporting). The p.Val581Phe variant in TCF4 occurs in the de novo state (biological parentage unconfirmed) in an individual with delays, hypotonia, not walking, dysmorphic features (University of Chicago internal database) (PM6). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Val581Phe variant in TCF4 has been observed in at least 2 individuals with neurodevelopmental phenotype (University of Chicago internal database, Invitae internal database) (PS4_supporting). In summary, the p.Val581Phe variant in TCF4 is classified as likely pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM1, PM2_supporting, PM6, PP3, PS4_supporting).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9995 | likely pathogenic ✓ concordant with ClinVar · top 3% in TCF4 |
|---|---|---|
| REVEL | 0.963 | strongly pathogenic-leaning |
| SaProt | LLR -10.53 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 7.6 | GERP 2.9, phastCons 1 |
| Regional constraint | o/e 0.15 | constrained · MANE · 740 bp · p 6.4e-20 · regional, not allelic |
| Overall | ||
| CADD | 33.0 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V577F vs ClinVar V581F) — verify the residue.
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.Val581Phe
- Coding
- c.1741G>T
- MANE Select
- NM_001083962
- dbSNP
- rs587784460
- Type
- single nucleotide variant
- Location
- chr18:55228985 (GRCh38)
- Gene constraint
- LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 52.08 · 5 PDB
- Residue 577 UniProt numbering
- the bhlh domain; a UniProt-annotated variant site (in pths); an α-helix
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-val581phe (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown