Is TFEB p.Arg8Pro (c.23G>C) pathogenic?

TFEB p.Arg8Pro (c.23G>C) is classified Uncertain significance in TFEB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-29). AlphaMissense: likely pathogenic (0.9927); Absent from gnomAD v4.1.

How common is TFEB p.Arg8Pro (c.23G>C) in the general population?

TFEB p.Arg8Pro (c.23G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TFEB p.Arg8Pro (c.23G>C)?

AlphaMissense predicts likely pathogenic (score 0.9927) — an in-silico prediction, not a clinical call.

TFEB p.Arg8Pro

c.23G>C · VCV3967962

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9927 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9927	likely pathogenic · top 8% in TFEB
REVEL	0.472	indeterminate
SaProt	LLR -11.70	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 7.2, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 3,437 bp · p 0.0002 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: TFEB
Protein: p.Arg8Pro
Coding: c.23G>C
MANE Select: NM_001271944
Type: single nucleotide variant
Location: chr6:41691191 (GRCh38)
Gene constraint: LOEUF 0.467 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.95 · 4 PDB
Residue 8: the 'interaction with acss2' region; the 'disordered' region; an α-helix

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

Similar variants

TFEB p.Ala111Thr Uncertain significance ★ ⚠ same type
TFEB p.Ala265Thr Uncertain significance ★ ⚠ same type
TFEB p.Arg220Pro Uncertain significance ★ ⚠ same type
TFEB p.Arg234Gln Uncertain significance ★ ⚠ same type
TFEB p.Arg303His Uncertain significance ★ ⚠ same type
TFEB p.Arg465Gln Uncertain significance ★ ⚠ same type
TFEB p.Asn182Asp Uncertain significance ★ ⚠ same type
TFEB p.Asn54Lys 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/tfeb-p-arg8pro (accessed [today's date]).

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