Is TCF3 p.Ala331= (c.993C>T) pathogenic?

TCF3 p.Ala331= (c.993C>T) is classified Likely benign in TCF3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-31). Ultra-rare (popmax 0.0168%, mid).

How common is TCF3 p.Ala331= (c.993C>T) in the general population?

TCF3 p.Ala331= (c.993C>T) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

TCF3 p.Ala331=

c.993C>T · rs372150270 · VCV2055480

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.81	GERP -3.5, phastCons 1
Overall
CADD	3.263	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0168% Middle Eastern · 1/5,950 alleles

Filtering AF 0.00306% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00208%

Overall 0.00312% 48/1,540,114 alleles · ultra-rare exomes 46/1,387,914 · genomes 2/152,200 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,950
Remaining individualsnot grpmax-eligible	0.00834%	11,986
South Asian	0.00714%	13,997
Admixed American	0.00393%	25,471
European (non-Finnish)	0.00297%	33,701

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.Ala331=
Coding: c.993C>T
MANE Select: NM_003200
dbSNP: rs372150270
Type: single nucleotide variant
Location: chr19:1621154 (GRCh38)
Gene constraint: LOEUF 1.239 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.42 · 5 PDB
Residue 331: a UniProt-annotated variant site (in agm8b; decreased protein abundance)

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

Similar variants

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
TCF3 p.Ala109Ser Uncertain significance ★★ ⚠ same type
TCF3 p.Ala115Thr 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-ala331 (accessed [today's date]).

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