TCF4 p.Ala192=
c.576C>A · rs143993583 · VCV1129740
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00856%, nfe)
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 8.7 | GERP 2, phastCons 1 |
| Overall | ||
| CADD | 12.52 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00856%
European (non-Finnish) · 101/1,179,910 alleles
Filtering AF
0.00716%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00668%
Overall
0.00657%
106/1,613,788 alleles · very rare
exomes 105/1,461,690 · genomes 1/152,098 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.00856% | 11,682 |
| Remaining individualsnot grpmax-eligible | 0.0064% | 15,618 |
| Finnishnot grpmax-eligible | 0.00156% | 64,026 |
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.Ala192=
- Coding
- c.576C>A
- MANE Select
- NM_001083962
- dbSNP
- rs143993583
- Type
- single nucleotide variant
- Location
- chr18:55279630 (GRCh38)
- Gene constraint
- LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 52.08 · 5 PDB
- Residue 192
- 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-ala192 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown