Is TCF3 p.Phe293Ser (c.878T>C) pathogenic?

TCF3 p.Phe293Ser (c.878T>C) is classified Conflicting classifications of pathogenicity in TCF3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-17). AlphaMissense: ambiguous (0.4013); Ultra-rare (popmax 0.0831%, mid).

How common is TCF3 p.Phe293Ser (c.878T>C) in the general population?

TCF3 p.Phe293Ser (c.878T>C) is ultra-rare (popmax 0.0831%, mid) (gnomAD).

What do computational predictors say about TCF3 p.Phe293Ser (c.878T>C)?

AlphaMissense predicts ambiguous (score 0.4013) — an in-silico prediction, not a clinical call.

TCF3 p.Phe293Ser

c.878T>C · rs141542090 · VCV1400310

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4013 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0831%, mid)

Computational evidence

Protein change
AlphaMissense	0.4013	ambiguous
REVEL	0.373	indeterminate
SaProt	LLR -5.21	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 39 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0831% Middle Eastern · 5/6,020 alleles

Filtering AF 0.0449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0401%

Overall 0.0127% 204/1,603,082 alleles · ultra-rare exomes 159/1,450,974 · genomes 45/152,108 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0831%	1,204
African / African-American	0.0588%	1,702
Admixed American	0.0342%	2,923
Remaining individualsnot grpmax-eligible	0.0145%	6,893
European (non-Finnish)	0.0102%	9,801
East Asian	0.0045%	22,224
Ashkenazi Jewishnot grpmax-eligible	0.00342%	29,272
South Asian	0.00336%	29,728

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.Phe293Ser
Coding: c.878T>C
MANE Select: NM_003200
dbSNP: rs141542090
Type: single nucleotide variant
Location: chr19:1621915 (GRCh38)
Gene constraint: LOEUF 1.239 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.42 · 5 PDB
Residue 293: 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.Phe293Leu Uncertain significance ★★ ⚠ same residue
TCF3 p.Phe293= Likely benign ★ same residue
TCF3 p.Phe293del 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

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-phe293ser (accessed [today's date]).

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