Is TCF3 p.Pro448Ala (c.1342C>G) pathogenic?

TCF3 p.Pro448Ala (c.1342C>G) is classified Uncertain significance in TCF3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-24). AlphaMissense: likely benign (0.0486); Ultra-rare (popmax 0.0268%, amr); Associated with Inborn genetic diseases.

What condition is associated with TCF3 p.Pro448Ala (c.1342C>G)?

TCF3 p.Pro448Ala (c.1342C>G) is associated with Inborn genetic diseases (ClinVar).

How common is TCF3 p.Pro448Ala (c.1342C>G) in the general population?

TCF3 p.Pro448Ala (c.1342C>G) is ultra-rare (popmax 0.0268%, amr) (gnomAD).

What do computational predictors say about TCF3 p.Pro448Ala (c.1342C>G)?

AlphaMissense predicts likely benign (score 0.0486) — an in-silico prediction, not a clinical call.

TCF3 p.Pro448Ala

c.1342C>G · rs879255378 · VCV252616

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0486 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0268%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0486	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -6.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.18	GERP -2.8, phastCons 0.017
Regional constraint	o/e 1.15	unconstrained · MANE · 39 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	0.056	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0268% Admixed American · 16/59,712 alleles

Filtering AF 0.0168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00132% 21/1,596,542 alleles · ultra-rare exomes 6/1,444,316 · genomes 15/152,226 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0268%	3,732
Remaining individualsnot grpmax-eligible	0.00483%	20,713
African / African-American	0.00267%	37,432

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.Pro448Ala
Coding: c.1342C>G
MANE Select: NM_003200
dbSNP: rs879255378
Type: single nucleotide variant
Location: chr19:1619219 (GRCh38)
Gene constraint: LOEUF 1.239 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.42 · 5 PDB
Residue 448: a UniProt-annotated variant site (in agm8b; decreased protein abundance)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TCF3 p.Pro448Ser Uncertain significance ★ ⚠ same residue
TCF3 p.Pro448= Likely benign ★ same residue
TCF3 p.Ala109Ser Uncertain significance ★★ ⚠ same condition
TCF3 p.Ala115Thr Uncertain significance ★★ ⚠ same condition
TCF3 p.Ala225Thr Uncertain significance ★★ ⚠ same condition
TCF3 p.Ala281Thr Uncertain significance ★★ ⚠ same condition
TCF3 p.Ala290Thr Uncertain significance ★★ ⚠ same condition
TCF3 p.Ala296Asp Uncertain significance ★★ ⚠ same condition

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-pro448ala (accessed [today's date]).

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