Is TCF4 p.Pro478Ala (c.1432C>G) pathogenic?

TCF4 p.Pro478Ala (c.1432C>G) is classified Likely benign in TCF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-09). AlphaMissense: likely benign (0.1341); Very rare (popmax 0.0011%, sas); Associated with Pitt-Hopkins syndrome.

What condition is associated with TCF4 p.Pro478Ala (c.1432C>G)?

TCF4 p.Pro478Ala (c.1432C>G) is associated with Pitt-Hopkins syndrome (ClinVar).

How common is TCF4 p.Pro478Ala (c.1432C>G) in the general population?

TCF4 p.Pro478Ala (c.1432C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about TCF4 p.Pro478Ala (c.1432C>G)?

AlphaMissense predicts likely benign (score 0.1341) — an in-silico prediction, not a clinical call.

TCF4 p.Pro478Ala

c.1432C>G · rs2144677083 · VCV1479245

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1341 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Pitt-Hopkins syndrome

Computational evidence

Protein change
AlphaMissense	0.1341	likely benign
REVEL	0.166	moderately benign-leaning
SaProt	LLR -7.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 26 kb · p 0.00081 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,072 alleles

Overall 6.2e-05% 1/1,614,118 alleles · very rare exomes 1/1,461,884 · genomes 0/152,234 · joint denominator

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.Pro478Ala
Coding: c.1432C>G
MANE Select: NM_001083962
dbSNP: rs2144677083
Type: single nucleotide variant
Location: chr18:55234602 (GRCh38)
Gene constraint: LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.08 · 5 PDB
Residue 478: 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.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
TCF4 p.Leu609Pro 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-pro478ala (accessed [today's date]).

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