Is TCF4 p.Asp517= (c.1551C>T) pathogenic?

TCF4 p.Asp517= (c.1551C>T) is classified Benign/Likely benign in TCF4 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-19). Rare (popmax 0.181%, sas); Associated with Inborn genetic diseases.

What condition is associated with TCF4 p.Asp517= (c.1551C>T)?

TCF4 p.Asp517= (c.1551C>T) is associated with Inborn genetic diseases, Pitt-Hopkins syndrome (ClinVar).

How common is TCF4 p.Asp517= (c.1551C>T) in the general population?

TCF4 p.Asp517= (c.1551C>T) is rare (popmax 0.181%, sas) (gnomAD).

TCF4 p.Asp517=

c.1551C>T · rs140862252 · VCV139409

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.181%, sas)

Conditions

Inborn genetic diseases

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 -4.7	GERP -5.5
Overall
CADD	0.514	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.181% South Asian · 165/91,078 alleles

Filtering AF 0.159% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.15%

Overall 0.0421% 679/1,614,028 alleles · rare exomes 652/1,461,876 · genomes 27/152,152 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.181%	552
Remaining individualsnot grpmax-eligible	0.0416%	2,404
European (non-Finnish)	0.0409%	2,443
Admixed American	0.005%	20,003
African / African-American	0.00267%	37,496

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: TCF4
Protein: p.Asp517=
Coding: c.1551C>T
MANE Select: NM_001083962
dbSNP: rs140862252
Type: single nucleotide variant
Location: chr18:55232607 (GRCh38)
Gene constraint: LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.08 · 5 PDB
Residue 517: a UniProt-annotated variant site (in pths); the 'disordered' region

Full TCF4 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

Also linked: Pitt-Hopkins syndrome

Similar variants

TCF4 p.Arg576Gln Pathogenic ★★★ same condition
TCF4 p.Arg578His Pathogenic ★★★ same condition
TCF4 p.Arg580Gln Pathogenic ★★★ same condition
TCF4 p.Arg580Trp Pathogenic ★★★ same condition
TCF4 p.Arg582Cys Likely pathogenic ★★★ same condition
TCF4 p.Gly496Cys Likely pathogenic ★★★ ⚠ same condition
TCF4 p.Gly592Ser Likely pathogenic ★★★ same condition
TCF4 p.Leu609Pro Likely pathogenic ★★★ 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/tcf4-p-asp517 (accessed [today's date]).

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