Is TCF4 p.Glu577= (c.1731G>A) pathogenic?

TCF4 p.Glu577= (c.1731G>A) is classified Likely benign in TCF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-25). Absent from gnomAD v4.1; Associated with Pitt-Hopkins syndrome.

What condition is associated with TCF4 p.Glu577= (c.1731G>A)?

TCF4 p.Glu577= (c.1731G>A) is associated with Pitt-Hopkins syndrome (ClinVar).

How common is TCF4 p.Glu577= (c.1731G>A) in the general population?

TCF4 p.Glu577= (c.1731G>A) is absent from gnomAD v4.1 (gnomAD).

TCF4 p.Glu577=

c.1731G>A · rs2144406756 · VCV1535173

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 0.24	GERP -0.78, phastCons 0.98
Overall
CADD	8.023	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TCF4
Protein: p.Glu577=
Coding: c.1731G>A
MANE Select: NM_001083962
dbSNP: rs2144406756
Type: single nucleotide variant
Location: chr18:55228995 (GRCh38)
Gene constraint: LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.08 · 5 PDB
Residue 577: the bhlh domain; a UniProt-annotated variant site (in pths); an α-helix

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.Glu577Gln Likely pathogenic ★ same residue
TCF4 p.Glu577Gly 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-glu577 (accessed [today's date]).

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