Is TCF4 p.Ser653fs (c.1957_1958del) pathogenic?

TCF4 p.Ser653fs (c.19571958del) is classified Pathogenic in TCF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-01-06). No gnomAD frequency available for this variant; Associated with Pitt-Hopkins syndrome.

What condition is associated with TCF4 p.Ser653fs (c.1957_1958del)?

TCF4 p.Ser653fs (c.1957_1958del) is associated with Pitt-Hopkins syndrome (ClinVar).

How common is TCF4 p.Ser653fs (c.1957_1958del) in the general population?

TCF4 p.Ser653fs (c.1957_1958del) is no gnomAD frequency available for this variant (gnomAD).

TCF4 p.Ser653fs

c.1957_1958del · rs1135401807 · VCV431137

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Pitt-Hopkins syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 19 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.95	GERP -0.91, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TCF4
Protein: p.Ser653fs
Coding: c.1957_1958del
MANE Select: NM_001083962
dbSNP: rs1135401807
Type: Microsatellite
Location: chr18:55228283 (GRCh38)
Gene constraint: LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.08 · 5 PDB
Residue 653: 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 c.*4214GTTTTT[3] Benign ★★★ same condition
TCF4 p.Ile248fs Pathogenic ★★ same condition
TCF4 p.Lys172fs Pathogenic ★★ same condition
TCF4 p.Ala357fs Likely pathogenic ★ same condition
TCF4 p.Gly496fs Likely pathogenic ★ same condition
TCF4 p.Thr210fs Pathogenic ★ same condition
TCF4 c.72+8_72+11del Conflicting classifications of pathogenicity ★ same condition
TCF4 p.Arg576Gln 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-ser653fs (accessed [today's date]).

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