Is TCF7 p.Pro375Arg (c.1124C>G) pathogenic?

TCF7 p.Pro375Arg (c.1124C>G) is classified Uncertain significance in TCF7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). Very rare (popmax 6.2e-05%).

How common is TCF7 p.Pro375Arg (c.1124C>G) in the general population?

TCF7 p.Pro375Arg (c.1124C>G) is very rare (popmax 6.2e-05%) (gnomAD).

TCF7 p.Pro375Arg

c.1124C>G · VCV3966503

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.529	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.75, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 3,273 bp · p 0.9 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,614,192 alleles · very rare exomes 1/1,461,890 · genomes 0/152,302 · 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: TCF7
Protein: p.Pro375Arg
Coding: c.1124C>G
MANE Select: NM_003202
Type: single nucleotide variant
Location: chr5:134146272 (GRCh38)
Gene constraint: LOEUF 0.624 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 58.11

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-pro375arg (accessed [today's date]).

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