Is MITF p.Glu333= (c.999A>G) pathogenic?

MITF p.Glu333= (c.999A>G) is classified Likely benign in MITF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-23). Very rare (popmax 8.48e-05%, nfe); Associated with Tietz syndrome.

What condition is associated with MITF p.Glu333= (c.999A>G)?

MITF p.Glu333= (c.999A>G) is associated with Tietz syndrome, Waardenburg syndrome type 2A, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Glu333= (c.999A>G) in the general population?

MITF p.Glu333= (c.999A>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

MITF p.Glu333=

c.999A>G · rs751770123 · VCV2921332

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Tietz syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -1.4, phastCons 1
Overall
CADD	9.19	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,746 alleles

Overall 6.84e-05% 1/1,461,450 alleles · very rare

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: MITF
Protein: p.Glu333=
Coding: c.999A>G
MANE Select: NM_001354604
dbSNP: rs751770123
Type: single nucleotide variant
Location: chr3:69956498 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 333: the bhlh domain; an α-helix

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

Disease context

Tietz syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Waardenburg syndrome type 2A melanoma, cutaneous malignant, susceptibility to, 8 hereditary neoplastic syndrome

Similar variants

MITF p.Glu333Ter Pathogenic/Likely pathogenic ★★ same residue
MITF p.Glu333Lys Uncertain significance ★★ ⚠ same residue
MITF p.Glu333fs Pathogenic ★ same residue
MITF c.1031+1G>A Pathogenic ★★ same condition
MITF c.1179+1G>A Pathogenic ★★ same condition
MITF c.355-1062G>C Pathogenic/Likely pathogenic ★★ same condition
MITF c.880+1G>A Likely pathogenic ★★ same condition
MITF c.955+1G>A Likely pathogenic ★★ 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/mitf-p-glu333 (accessed [today's date]).

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