Is TFEB p.Pro388Ser (c.1162C>T) pathogenic?

TFEB p.Pro388Ser (c.1162C>T) is classified Uncertain significance in TFEB (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-17). AlphaMissense: likely benign (0.0633); Ultra-rare (popmax 0.0406%, afr).

How common is TFEB p.Pro388Ser (c.1162C>T) in the general population?

TFEB p.Pro388Ser (c.1162C>T) is ultra-rare (popmax 0.0406%, afr) (gnomAD).

What do computational predictors say about TFEB p.Pro388Ser (c.1162C>T)?

AlphaMissense predicts likely benign (score 0.0633) — an in-silico prediction, not a clinical call.

TFEB p.Pro388Ser

c.1162C>T · rs529500196 · VCV2393070

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0633 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0406%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0633	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -6.75	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 6.2	GERP 4.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 361 bp · p 0.58 · regional, not allelic
Overall
CADD	12.21	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 0.0406% African / African-American · 30/73,976 alleles

Filtering AF 0.0292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0253%

Overall 0.00191% 30/1,570,662 alleles · ultra-rare exomes 11/1,418,316 · genomes 19/152,346 · 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: TFEB
Protein: p.Pro388Ser
Coding: c.1162C>T
MANE Select: NM_001271944
dbSNP: rs529500196
Type: single nucleotide variant
Location: chr6:41684868 (GRCh38)
Gene constraint: LOEUF 0.467 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.95 · 4 PDB
Residue 388: the 'disordered' region

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

Similar variants

TFEB p.Pro388Leu Uncertain significance ★ ⚠ same residue
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

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-pro388ser (accessed [today's date]).

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