Is TCF4 p.Ser529= (c.1587G>A) pathogenic?

TCF4 p.Ser529= (c.1587G>A) is classified Likely benign in TCF4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-20). Very rare (popmax 0.00533%, afr); Associated with Pitt-Hopkins syndrome.

What condition is associated with TCF4 p.Ser529= (c.1587G>A)?

TCF4 p.Ser529= (c.1587G>A) is associated with Pitt-Hopkins syndrome (ClinVar).

How common is TCF4 p.Ser529= (c.1587G>A) in the general population?

TCF4 p.Ser529= (c.1587G>A) is very rare (popmax 0.00533%, afr) (gnomAD).

TCF4 p.Ser529=

c.1587G>A · rs567457339 · VCV385572

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

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 -0.12	GERP -5.5, phastCons 0.082
Overall
CADD	7.547	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00533% African / African-American · 4/75,026 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00118% 19/1,614,132 alleles · very rare exomes 17/1,461,874 · genomes 2/152,258 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00533%	18,756
East Asian	0.00223%	44,882
European (non-Finnish)	0.00119%	84,286

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: TCF4
Protein: p.Ser529=
Coding: c.1587G>A
MANE Select: NM_001083962
dbSNP: rs567457339
Type: single nucleotide variant
Location: chr18:55232571 (GRCh38)
Gene constraint: LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.08 · 5 PDB
Residue 529: 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

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

Similar variants

TCF4 p.Ser529Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TCF4 p.Ser529fs 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

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-ser529 (accessed [today's date]).

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