Is TCF3 p.Pro353= (c.1059T>G) pathogenic?

TCF3 p.Pro353= (c.1059T>G) is classified Likely benign in TCF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-17). Ultra-rare (popmax 0.0676%, amr).

How common is TCF3 p.Pro353= (c.1059T>G) in the general population?

TCF3 p.Pro353= (c.1059T>G) is ultra-rare (popmax 0.0676%, amr) (gnomAD).

TCF3 p.Pro353=

c.1059T>G · rs759068741 · VCV725851

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0676%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.8	GERP -3.9, phastCons 1
Overall
CADD	0.861	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0676% Admixed American · 29/42,868 alleles

Filtering AF 0.0483% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0419%

Overall 0.00264% 40/1,516,462 alleles · ultra-rare exomes 14/1,364,352 · genomes 26/152,110 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0676%	1,478
Remaining individualsnot grpmax-eligible	0.0171%	5,841
African / African-American	0.00141%	70,850

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.Pro353=
Coding: c.1059T>G
MANE Select: NM_003200
dbSNP: rs759068741
Type: single nucleotide variant
Location: chr19:1621002 (GRCh38)
Gene constraint: LOEUF 1.239 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.42 · 5 PDB
Residue 353: a UniProt-annotated variant site (in agm8b; decreased protein abundance); the 'disordered' region

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

Similar variants

TCF3 p.Pro353Leu Uncertain significance ★★ same residue
TCF3 p.Pro353Ser 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

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-pro353 (accessed [today's date]).

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