Is TCF7 p.Pro153Arg (c.458C>G) pathogenic?

TCF7 p.Pro153Arg (c.458C>G) is classified Uncertain significance in TCF7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-05). Very rare (popmax 0.00684%, amr).

How common is TCF7 p.Pro153Arg (c.458C>G) in the general population?

TCF7 p.Pro153Arg (c.458C>G) is very rare (popmax 0.00684%, amr) (gnomAD).

TCF7 p.Pro153Arg

c.458C>G · rs144072187 · VCV3175165

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00684%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.68	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.42, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 28 kb · p 5.9e-05 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00684% Admixed American · 4/58,452 alleles

Filtering AF 0.0023% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00199%

Overall 0.00293% 47/1,603,524 alleles · very rare exomes 45/1,451,514 · genomes 2/152,010 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00684%	14,613
South Asian	0.00447%	22,389
Finnishnot grpmax-eligible	0.00313%	31,933
European (non-Finnish)	0.00306%	32,630
Remaining individualsnot grpmax-eligible	0.00161%	62,040

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.Pro153Arg
Coding: c.458C>G
MANE Select: NM_003202
dbSNP: rs144072187
Type: single nucleotide variant
Location: chr5:134138075 (GRCh38)
Gene constraint: LOEUF 0.624 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 58.11
Residue 153: the 'disordered' region

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

Similar variants

TCF7 p.Pro153His Uncertain significance ★ same residue
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

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-pro153arg (accessed [today's date]).

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