Is TCF3 p.Pro353Ser (c.1057C>T) pathogenic?

TCF3 p.Pro353Ser (c.1057C>T) is classified Uncertain significance in TCF3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-03). AlphaMissense: likely benign (0.1609); Very rare (popmax 0.00912%, amr); Associated with Inborn genetic diseases.

What condition is associated with TCF3 p.Pro353Ser (c.1057C>T)?

TCF3 p.Pro353Ser (c.1057C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TCF3 p.Pro353Ser (c.1057C>T) in the general population?

TCF3 p.Pro353Ser (c.1057C>T) is very rare (popmax 0.00912%, amr) (gnomAD).

What do computational predictors say about TCF3 p.Pro353Ser (c.1057C>T)?

AlphaMissense predicts likely benign (score 0.1609) — an in-silico prediction, not a clinical call.

TCF3 p.Pro353Ser

c.1057C>T · rs1358474096 · VCV1912885

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1609 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00912%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1609	likely benign
REVEL	0.386	indeterminate
SaProt	LLR -5.36	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 39 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	24.3	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 0.00912% Admixed American · 4/43,862 alleles

Filtering AF 0.00303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00131% 20/1,520,910 alleles · very rare exomes 20/1,368,586 · genomes 0/152,324 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00912%	10,966
Remaining individualsnot grpmax-eligible	0.00341%	29,299
South Asian	0.00127%	78,742
European (non-Finnish)	0.00115%	87,286

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.Pro353Ser
Coding: c.1057C>T
MANE Select: NM_003200
dbSNP: rs1358474096
Type: single nucleotide variant
Location: chr19:1621004 (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

Disease context

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

Similar variants

TCF3 p.Pro353Leu Uncertain significance ★★ same residue
TCF3 p.Pro353= 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-pro353ser (accessed [today's date]).

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