Is TCF7 p.Pro20Ser (c.58C>T) pathogenic?

TCF7 p.Pro20Ser (c.58C>T) is classified Uncertain significance in TCF7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-07). Ultra-rare (popmax 0.019%, amr).

How common is TCF7 p.Pro20Ser (c.58C>T) in the general population?

TCF7 p.Pro20Ser (c.58C>T) is ultra-rare (popmax 0.019%, amr) (gnomAD).

TCF7 p.Pro20Ser

c.58C>T · rs1048236309 · VCV2219194

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.019%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.296	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 0.93, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 28 kb · p 5.9e-05 · regional, not allelic
Overall
CADD	19.92	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.019% Admixed American · 6/31,582 alleles

Filtering AF 0.0082% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00556%

Overall 0.000682% 8/1,172,252 alleles · ultra-rare exomes 3/1,025,516 · genomes 5/146,736 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.019%	5,264
European (non-Finnish)	0.000216%	464,022

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: TCF7
Protein: p.Pro20Ser
Coding: c.58C>T
MANE Select: NM_003202
dbSNP: rs1048236309
Type: single nucleotide variant
Location: chr5:134114964 (GRCh38)
Gene constraint: LOEUF 0.624 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 58.11
Residue 20: the 'disordered' region; the 'ctnnb1-binding' region

Full TCF7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TCF7 p.Ala109Ser Uncertain significance ★ same type
TCF7 p.Ala150Thr Uncertain significance ★ same type
TCF7 p.Ala364Thr Uncertain significance ★ same type
TCF7 p.Ala373Thr Uncertain significance ★ same type
TCF7 p.Ala41Thr Uncertain significance ★ same type
TCF7 p.Ala42Val Uncertain significance ★ same type
TCF7 p.Ala74Thr Uncertain significance ★ same type
TCF7 p.Ala78Thr Uncertain significance ★ 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/tcf7-p-pro20ser (accessed [today's date]).

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