TCF3 p.Ala424=
c.1272G>A · rs759590377 · VCV2722057
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0204%, mid)
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 -11 | GERP -2.4 |
| Overall | ||
| CADD | 2.119 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0204%
Middle Eastern · 1/4,914 alleles
Filtering AF
0.00497%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00457%
Overall
0.00567%
90/1,588,182 alleles · ultra-rare
exomes 83/1,435,946 · genomes 7/152,236 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0204% | 4,914 |
| East Asian | 0.00676% | 14,800 |
| South Asian | 0.00666% | 15,014 |
| European (non-Finnish) | 0.00613% | 16,310 |
| African / African-American | 0.00536% | 18,662 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00341% | 29,320 |
| Admixed American | 0.00339% | 29,504 |
| Remaining individualsnot grpmax-eligible | 0.00162% | 61,638 |
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
- TCF3
- Protein
- p.Ala424=
- Coding
- c.1272G>A
- MANE Select
- NM_003200
- dbSNP
- rs759590377
- Type
- single nucleotide variant
- Location
- chr19:1619370 (GRCh38)
- Gene constraint
- LOEUF 1.239 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 52.42 · 5 PDB
- Residue 424
- a UniProt-annotated variant site (in agm8b; decreased protein abundance); the 'leucine-zipper' region
Similar variants
- TCF3 p.Ala424Val Benign/Likely benign ★★ same residue
- TCF3 p.Arg321Ter Pathogenic ★★ same type
- TCF3 p.Glu555Lys Pathogenic ★★ same type
- TCF3 c.1327-3C>A Uncertain significance ★★ same type
- TCF3 c.652+5A>G Uncertain significance ★★ same type
- TCF3 c.955+3A>G Uncertain significance ★★ same type
- TCF3 c.955+6G>A Uncertain significance ★★ same type
- TCF3 p.Ala109Ser Uncertain significance ★★ ⚠ same type
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/tcf3-p-ala424 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown