Is TG p.Leu415Pro (c.1244T>C) pathogenic?

TG p.Leu415Pro (c.1244T>C) is classified Uncertain significance in TG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-19). AlphaMissense: ambiguous (0.4134); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TG p.Leu415Pro (c.1244T>C)?

TG p.Leu415Pro (c.1244T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TG p.Leu415Pro (c.1244T>C) in the general population?

TG p.Leu415Pro (c.1244T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TG p.Leu415Pro (c.1244T>C)?

AlphaMissense predicts ambiguous (score 0.4134) — an in-silico prediction, not a clinical call.

TG p.Leu415Pro

c.1244T>C · VCV4183515

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4134 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4134	ambiguous
REVEL	0.699	pathogenic-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 268 kb · p 0.022 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

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: TG
Protein: p.Leu415Pro
Coding: c.1244T>C
MANE Select: NM_003235
Type: single nucleotide variant
Location: chr8:132886616 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Residue 415: an α-helix; a disulfide bond

Full TG 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

TG p.Ala1033Val Uncertain significance ★★ ⚠ same condition
TG p.Ala1419Glu Uncertain significance ★★ same condition
TG p.Ala1419Val Uncertain significance ★★ ⚠ same condition
TG p.Ala1583Val Uncertain significance ★★ ⚠ same condition
TG p.Ala1631Ser Uncertain significance ★★ ⚠ same condition
TG p.Ala402Gly Uncertain significance ★★ ⚠ same condition
TG p.Ala457Val Uncertain significance ★★ same condition
TG p.Arg1066Cys 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/tg-p-leu415pro (accessed [today's date]).

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