Is TFEB p.Arg220Pro (c.659G>C) pathogenic?

TFEB p.Arg220Pro (c.659G>C) is classified Uncertain significance in TFEB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: ambiguous (0.4384); Very rare (popmax 0.0033%, sas).

How common is TFEB p.Arg220Pro (c.659G>C) in the general population?

TFEB p.Arg220Pro (c.659G>C) is very rare (popmax 0.0033%, sas) (gnomAD).

What do computational predictors say about TFEB p.Arg220Pro (c.659G>C)?

AlphaMissense predicts ambiguous (score 0.4384) — an in-silico prediction, not a clinical call.

TFEB p.Arg220Pro

c.659G>C · VCV4183412

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4384 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4384	ambiguous
REVEL	0.205	benign-leaning
SaProt	LLR -10.36	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2.8, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 3,437 bp · p 0.0002 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0033% South Asian · 3/91,032 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000992% 16/1,613,632 alleles · very rare exomes 15/1,461,442 · genomes 1/152,190 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,344
African / African-American	0.00267%	37,461
European (non-Finnish)	0.000932%	107,252

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.Arg220Pro
Coding: c.659G>C
MANE Select: NM_001271944
Type: single nucleotide variant
Location: chr6:41687919 (GRCh38)
Gene constraint: LOEUF 0.467 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.95 · 4 PDB

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.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
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-arg220pro (accessed [today's date]).

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