Is MITF p.Glu523= (c.1569G>A) pathogenic?

MITF p.Glu523= (c.1569G>A) is classified Benign/Likely benign in MITF (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-02). Low-frequency (popmax 2.66%, sas); Associated with Waardenburg syndrome type 2A.

What condition is associated with MITF p.Glu523= (c.1569G>A)?

MITF p.Glu523= (c.1569G>A) is associated with Waardenburg syndrome type 2A, Tietz syndrome, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Glu523= (c.1569G>A) in the general population?

MITF p.Glu523= (c.1569G>A) is low-frequency (popmax 2.66%, sas) (gnomAD).

MITF p.Glu523=

c.1569G>A · rs200830148 · VCV346501

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.66%, sas)

Conditions

Waardenburg syndrome type 2A

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 1.7	GERP -0.66, phastCons 1
Overall
CADD	1.53	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.66% South Asian · 2,426/91,082 alleles

Filtering AF 2.58% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.54%

Overall 0.159% 2,573/1,613,872 alleles · low-frequency exomes 2,435/1,461,556 · genomes 138/152,316 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	2.66%	38
Remaining individualsnot grpmax-eligible	0.192%	521
Middle Eastern	0.066%	1,514
East Asian	0.00446%	22,435
African / African-American	0.00267%	37,519
Admixed American	0.00167%	60,026
European (non-Finnish)	0.00153%	65,545

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.Glu523=
Coding: c.1569G>A
MANE Select: NM_001354604
dbSNP: rs200830148
Type: single nucleotide variant
Location: chr3:69965236 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 523: the 'disordered' region

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

Disease context

Waardenburg syndrome type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Tietz syndrome melanoma, cutaneous malignant, susceptibility to, 8 hereditary neoplastic syndrome

Similar variants

MITF p.Glu523Asp Uncertain significance ★ ⚠ same residue
MITF p.Glu523Gln Uncertain significance ★ ⚠ same residue
MITF p.Glu523Lys Uncertain significance ★ ⚠ 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-glu523 (accessed [today's date]).

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