Is TCF3 p.Asp535= (c.1605C>T) pathogenic?

TCF3 p.Asp535= (c.1605C>T) is classified Likely benign in TCF3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-07). Very rare (popmax 0.00167%, amr).

How common is TCF3 p.Asp535= (c.1605C>T) in the general population?

TCF3 p.Asp535= (c.1605C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

TCF3 p.Asp535=

c.1605C>T · VCV3607468

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.22	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7	GERP 0.62, phastCons 1
Overall
CADD	17.59	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,974 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000995% 16/1,608,548 alleles · very rare exomes 14/1,456,342 · genomes 2/152,206 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,215
Admixed Americangrpmax	0.00167%	59,974
African / African-American	0.00133%	74,942
South Asian	0.0011%	91,064
European (non-Finnish)	0.000932%	107,251

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp535=
Coding: c.1605C>T
MANE Select: NM_003200
Type: single nucleotide variant
Location: chr19:1615502 (GRCh38)
Gene constraint: LOEUF 1.239 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.42 · 5 PDB
Residue 535: 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.Leu535Pro Uncertain significance ★ same residue
TCF3 p.Leu535= Likely benign ★ same residue
TCF3 p.Leu535Val Likely benign ★ same residue
TCF3 p.Asp535_Asp536insGluAsp 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

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-asp535 (accessed [today's date]).

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