Is TCF4 p.Asp417= (c.1251C>T) pathogenic?

TCF4 p.Asp417= (c.1251C>T) is classified Likely benign in TCF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-21). Very rare (popmax 0.00834%, amr); Associated with Pitt-Hopkins syndrome.

What condition is associated with TCF4 p.Asp417= (c.1251C>T)?

TCF4 p.Asp417= (c.1251C>T) is associated with Pitt-Hopkins syndrome (ClinVar).

How common is TCF4 p.Asp417= (c.1251C>T) in the general population?

TCF4 p.Asp417= (c.1251C>T) is very rare (popmax 0.00834%, amr) (gnomAD).

TCF4 p.Asp417=

c.1251C>T · rs769451884 · VCV468946

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Conditions

Pitt-Hopkins syndrome

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 2.9	GERP -0.64, phastCons 1
Overall
CADD	10.56	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00834% Admixed American · 5/59,944 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000753% 11/1,461,460 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,989
African / African-American	0.004%	25,002
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.00017%	589,918

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.Asp417=
Coding: c.1251C>T
MANE Select: NM_001083962
dbSNP: rs769451884
Type: single nucleotide variant
Location: chr18:55254596 (GRCh38)
Gene constraint: LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.08 · 5 PDB
Residue 417: a UniProt-annotated variant site (in pths)

Full TCF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Pitt-Hopkins syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TCF4 p.Asp417fs Pathogenic ★ same residue
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

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-asp417 (accessed [today's date]).

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