Is TCF4 p.Pro236Ala (c.706C>G) pathogenic?

TCF4 p.Pro236Ala (c.706C>G) is classified Likely benign in TCF4 (ClinVar, Expert panel, 4 submitters; last evaluated 2024-06-25). AlphaMissense: likely benign (0.0533); Very rare (popmax 8.48e-05%, nfe); Associated with Pitt-Hopkins syndrome.

What condition is associated with TCF4 p.Pro236Ala (c.706C>G)?

TCF4 p.Pro236Ala (c.706C>G) is associated with Pitt-Hopkins syndrome (ClinVar).

How common is TCF4 p.Pro236Ala (c.706C>G) in the general population?

TCF4 p.Pro236Ala (c.706C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about TCF4 p.Pro236Ala (c.706C>G)?

AlphaMissense predicts likely benign (score 0.0533) — an in-silico prediction, not a clinical call.

TCF4 p.Pro236Ala

c.706C>G · rs139859596 · VCV373746

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0533 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Pitt-Hopkins syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Likely Benign for Pitt-Hopkins syndrome. Applied ACMG criteria (verbatim):

BS2 BP4

Curation rationale (ClinGen, verbatim)

The highest population minor allele frequency of the p.Pro236Ala variant in TCF4 in gnomAD v4.1 is 0.00000062 in the European (non-Finnish) population (not sufficient to meet BS1 criteria). The p.Pro236Ala variant is observed in at least 2 unaffected individuals (Internal database - GeneDx, Internal database - Ambry) (BS2). Computational analysis prediction tools suggest that the p.Pro236Ala variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Pro236Ala variant in TCF4 is classified as a likely benign variant based on the ACMG/AMP criteria (BS2, BP4).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0533	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -6.47	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 10	GERP 2.8, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 96 kb · p 1.2e-10 · regional, not allelic
Overall
CADD	23.1	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 8.48e-05% European (non-Finnish) · 1/1,179,834 alleles

Overall 6.2e-05% 1/1,613,798 alleles · very rare exomes 0/1,461,612 · genomes 1/152,186 · 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.Pro236Ala
Coding: c.706C>G
MANE Select: NM_001083962
dbSNP: rs139859596
Type: single nucleotide variant
Location: chr18:55275702 (GRCh38)
Gene constraint: LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.08 · 5 PDB
Residue 236: 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.Pro236Leu Uncertain significance ★ ⚠ same residue
TCF4 p.Pro236= Likely benign ★ 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-pro236ala (accessed [today's date]).

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