Is TFEB p.His129Arg (c.386A>G) pathogenic?

TFEB p.His129Arg (c.386A>G) is classified Uncertain significance in TFEB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: likely benign (0.0824); Ultra-rare (popmax 0.0166%, mid).

How common is TFEB p.His129Arg (c.386A>G) in the general population?

TFEB p.His129Arg (c.386A>G) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about TFEB p.His129Arg (c.386A>G)?

AlphaMissense predicts likely benign (score 0.0824) — an in-silico prediction, not a clinical call.

TFEB p.His129Arg

c.386A>G · VCV3455681

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0824 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0824	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -5.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 4.3, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 3,437 bp · p 0.0002 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0166% Middle Eastern · 1/6,014 alleles

Filtering AF 0.000293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000212%

Overall 0.000624% 10/1,603,532 alleles · ultra-rare exomes 10/1,451,206 · genomes 0/152,326 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,014
Remaining individualsnot grpmax-eligible	0.00161%	61,958
European (non-Finnish)	0.000682%	146,668

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: TFEB
Protein: p.His129Arg
Coding: c.386A>G
MANE Select: NM_001271944
Type: single nucleotide variant
Location: chr6:41690745 (GRCh38)
Gene constraint: LOEUF 0.467 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.95 · 4 PDB
Residue 129: the 'interaction with acss2' region; the 'disordered' region

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.Arg8Pro Uncertain significance ★ ⚠ same type
TFEB p.Asn182Asp 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-his129arg (accessed [today's date]).

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