TCF4 p.Glu22=
c.66G>A · rs113395332 · VCV327313
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 4 submitters
gnomAD v4.1
Rare
rare (popmax 0.768%, afr)
Conditions
1
Pitt-Hopkins syndrome
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 4.5 | GERP 1.5, phastCons 1 |
| Overall | ||
| CADD | 20.3 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.768%
African / African-American · 561/73,074 alleles
Filtering AF
0.715%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.694%
Overall
0.0429%
659/1,535,088 alleles · rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.768% | 130 |
| Admixed American | 0.0745% | 1,342 |
| Remaining individualsnot grpmax-eligible | 0.0584% | 1,714 |
| Middle Eastern | 0.0167% | 5,984 |
| South Asian | 0.00238% | 42,021 |
| European (non-Finnish) | 0.00192% | 52,117 |
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.Glu22=
- Coding
- c.66G>A
- MANE Select
- NM_001083962 · reported on NM_001243230
- dbSNP
- rs113395332
- Type
- single nucleotide variant
- Location
- chr18:55588470 (GRCh38)
- Gene constraint
- LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 52.08 · 5 PDB
- Residue 22
- the 'essential for myod1 inhibition' region; 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-glu22 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown