Is TCF4 p.Pro199Ser (c.595C>T) pathogenic?

TCF4 p.Pro199Ser (c.595C>T) is classified Uncertain significance in TCF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-20). AlphaMissense: likely benign (0.1886); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TCF4 p.Pro199Ser (c.595C>T)?

TCF4 p.Pro199Ser (c.595C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TCF4 p.Pro199Ser (c.595C>T) in the general population?

TCF4 p.Pro199Ser (c.595C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TCF4 p.Pro199Ser (c.595C>T)?

AlphaMissense predicts likely benign (score 0.1886) — an in-silico prediction, not a clinical call.

TCF4 p.Pro199Ser

c.595C>T · VCV3805085

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1886 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1886	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -4.91	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
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 0.64	unconstrained · MANE · 96 kb · p 1.2e-10 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TCF4
Protein: p.Pro199Ser
Coding: c.595C>T
MANE Select: NM_001083962
Type: single nucleotide variant
Location: chr18:55279611 (GRCh38)
Gene constraint: LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.08 · 5 PDB
Residue 199: 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

Similar variants

TCF4 p.Gln169Ter Pathogenic ★★ same condition
TCF4 p.Ala444Pro Uncertain significance ★★ ⚠ same condition
TCF4 p.Asp394His Uncertain significance ★★ ⚠ same condition
TCF4 p.Asp492Glu Uncertain significance ★★ ⚠ same condition
TCF4 p.Leu382Ser Uncertain significance ★★ ⚠ same condition
TCF4 p.Lys533Arg Uncertain significance ★★ ⚠ same condition
TCF4 p.Met233Ile Uncertain significance ★★ ⚠ same condition
TCF4 p.Met430Arg Uncertain significance ★★ ⚠ 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-pro199ser (accessed [today's date]).

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