Is TCF4 p.Pro490Ser (c.1468C>T) pathogenic?

TCF4 p.Pro490Ser (c.1468C>T) is classified Likely benign in TCF4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-15). AlphaMissense: likely benign (0.0521); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with TCF4 p.Pro490Ser (c.1468C>T)?

TCF4 p.Pro490Ser (c.1468C>T) is associated with Inborn genetic diseases, Pitt-Hopkins syndrome (ClinVar).

How common is TCF4 p.Pro490Ser (c.1468C>T) in the general population?

TCF4 p.Pro490Ser (c.1468C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TCF4 p.Pro490Ser (c.1468C>T)?

AlphaMissense predicts likely benign (score 0.0521) — an in-silico prediction, not a clinical call.

TCF4 p.Pro490Ser

c.1468C>T · rs375511149 · VCV1407605

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0521 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0521	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -5.07	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 9.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 26 kb · p 0.00081 · regional, not allelic
Overall
CADD	21.1	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 0.00167% Admixed American · 1/60,002 alleles

Overall 0.000124% 2/1,614,050 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,002
African / African-American	0.00133%	74,912

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.Pro490Ser
Coding: c.1468C>T
MANE Select: NM_001083962
dbSNP: rs375511149
Type: single nucleotide variant
Location: chr18:55234566 (GRCh38)
Gene constraint: LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.08 · 5 PDB
Residue 490: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Pitt-Hopkins syndrome

Similar variants

TCF4 p.Pro490Arg Likely pathogenic ★ ⚠ same residue
TCF4 p.Pro490Leu Uncertain significance ★ ⚠ 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-pro490ser (accessed [today's date]).

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