Is TCF4 p.Pro657fs (c.1966_1969dup) pathogenic?

TCF4 p.Pro657fs (c.19661969dup) is classified Pathogenic in TCF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2014-01-22). No gnomAD frequency available for this variant.

How common is TCF4 p.Pro657fs (c.1966_1969dup) in the general population?

TCF4 p.Pro657fs (c.1966_1969dup) is no gnomAD frequency available for this variant (gnomAD).

TCF4 p.Pro657fs

c.1966_1969dup · rs796053428 · VCV207544

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

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	escapes	premature termination codon within the last 50 nt of the penultimate exon (19 of 20, 50 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.9, 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.Pro657fs
Coding: c.1966_1969dup
MANE Select: NM_001083962
dbSNP: rs796053428
Type: Microsatellite
Location: chr18:55228271 (GRCh38)
Gene constraint: LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.08 · 5 PDB
Residue 657: a UniProt-annotated variant site (in pths); the 'disordered' region

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

Similar variants

TCF4 p.Pro657Ala Benign ★ same residue
TCF4 c.*4214GTTTTT[3] Benign ★★★ same type
TCF4 p.Ile248fs Pathogenic ★★ same type
TCF4 p.Lys172fs Pathogenic ★★ same type
TCF4 c.549+28099AG[2] Benign/Likely benign ★★ same type
TCF4 p.Ala357fs Likely pathogenic ★ same type
TCF4 p.Gly496fs Likely pathogenic ★ same type
TCF4 p.Ser381fs Pathogenic ★ same type

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-pro657fs (accessed [today's date]).

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