Is TCF3 p.Ser434= (c.1302A>G) pathogenic?

TCF3 p.Ser434= (c.1302A>G) is classified Benign in TCF3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 86.2%, eas) — too common for a highly-penetrant pathogenic allele.

TCF3 p.Ser434=

Q: How common is TCF3 p.Ser434= (c.1302A>G) in the general population?

TCF3 p.Ser434= (c.1302A>G) is common (popmax 86.2%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1302A>G · rs8140 · VCV1167431

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 86.2%, eas) — too common for a highly-penetrant pathogenic allele

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 -20	GERP -2.1
Overall
CADD	0.014	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 86.2% East Asian · 37,848/43,914 alleles

Filtering AF 85.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 85.2%

Overall 43.9% 692,002/1,577,618 alleles · common exomes 612,592/1,425,516 · genomes 79,410/152,102 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	86.2%	1
African / African-American	72.8%	1
Admixed American	51.7%	2
South Asian	45.1%	2
Remaining individualsnot grpmax-eligible	45.1%	2
Finnishnot grpmax-eligible	43.7%	2
Ashkenazi Jewishnot grpmax-eligible	41.9%	2
European (non-Finnish)	40%	3
Amishnot grpmax-eligible	34%	3
Middle Eastern	32.5%	3

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.Ser434=
Coding: c.1302A>G
MANE Select: NM_003200
dbSNP: rs8140
Type: single nucleotide variant
Location: chr19:1619340 (GRCh38)
Gene constraint: LOEUF 1.239 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.42 · 5 PDB
Residue 434: a UniProt-annotated variant site (in agm8b; decreased protein abundance)

Full TCF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TCF3 p.Ser434_Leu435= Uncertain significance ★ 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-ser434 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown