Is TCF3 p.Ser253= (c.759C>T) pathogenic?

TCF3 p.Ser253= (c.759C>T) is classified Benign in TCF3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 52.9%, afr) — too common for a highly-penetrant pathogenic allele.

TCF3 p.Ser253=

Q: How common is TCF3 p.Ser253= (c.759C>T) in the general population?

TCF3 p.Ser253= (c.759C>T) is common (popmax 52.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.759C>T · rs2240590 · VCV1167432

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 52.9%, afr) — 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	<0.2	all four deltas below 0.2 · G>C here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.25	GERP -1.5
Overall
CADD	7.333	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 52.9% African / African-American · 39,572/74,776 alleles

Filtering AF 52.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 52.3%

Overall 16.7% 267,886/1,599,406 alleles · common exomes 228,815/1,447,406 · genomes 39,071/152,000 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	52.9%	2
South Asian	34.5%	3
Admixed American	33.4%	3
East Asian	21.1%	5
Remaining individualsnot grpmax-eligible	17.9%	6
Middle Eastern	16.1%	6
European (non-Finnish)	12.6%	8
Finnishnot grpmax-eligible	9.78%	10
Ashkenazi Jewishnot grpmax-eligible	8.9%	11
Amishnot grpmax-eligible	4.73%	21

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.Ser253=
Coding: c.759C>T
MANE Select: NM_003200
dbSNP: rs2240590
Type: single nucleotide variant
Location: chr19:1622117 (GRCh38)
Gene constraint: LOEUF 1.239 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.42 · 5 PDB
Residue 253: the 'disordered' region

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

Similar variants

TCF3 p.Ser253Arg Uncertain significance ★ ⚠ same residue
TCF3 p.Ser253fs Pathogenic ★ 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

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-ser253 (accessed [today's date]).

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