TCF4 p.Arg580=
c.1740G>C · rs1298431147 · VCV2056884
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00133%, 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 -3.4 | GERP -5.9 |
| Overall | ||
| CADD | 5.622 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00133%
African / African-American · 1/74,930 alleles
Filtering AF
7.9e-05%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 5.4e-05%
Overall
0.00031%
5/1,614,072 alleles · very rare
exomes 3/1,461,880 · genomes 2/152,192 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.00133% | 74,930 |
| European (non-Finnish) | 0.000339% | 295,009 |
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.Arg580=
- Coding
- c.1740G>C
- MANE Select
- NM_001083962
- dbSNP
- rs1298431147
- Type
- single nucleotide variant
- Location
- chr18:55228986 (GRCh38)
- Gene constraint
- LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 52.08 · 5 PDB
- Residue 580
- the bhlh domain; a UniProt-annotated variant site (in pths); an α-helix
Similar variants
- TCF4 p.Arg580Gln Pathogenic ★★★ same residue
- TCF4 p.Arg580Trp Pathogenic ★★★ same residue
- TCF4 p.Arg580Leu Pathogenic/Likely pathogenic ★★ same residue
- TCF4 p.Arg576Gln Pathogenic ★★★ same condition
- TCF4 p.Arg578His Pathogenic ★★★ same condition
- TCF4 p.Arg582Cys Likely pathogenic ★★★ same condition
- TCF4 p.Gly496Cys Likely pathogenic ★★★ ⚠ same condition
- TCF4 p.Gly592Ser 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-arg580 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown