Is MITF p.Pro505= (c.1515C>T) pathogenic?

MITF p.Pro505= (c.1515C>T) is classified Likely benign in MITF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-03). Very rare (popmax 0.00446%, eas); Associated with Tietz syndrome.

What condition is associated with MITF p.Pro505= (c.1515C>T)?

MITF p.Pro505= (c.1515C>T) is associated with Tietz syndrome, Waardenburg syndrome type 2A, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Pro505= (c.1515C>T) in the general population?

MITF p.Pro505= (c.1515C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

MITF p.Pro505=

c.1515C>T · rs761127025 · VCV1203045

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

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 -14	GERP -4.3
Overall
CADD	1.087	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,862 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00205% 33/1,613,552 alleles · very rare exomes 27/1,461,448 · genomes 6/152,104 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,431
South Asian	0.0033%	30,347
African / African-American	0.00267%	37,447
European (non-Finnish)	0.00203%	49,154
Admixed American	0.00167%	59,990
Remaining individualsnot grpmax-eligible	0.0016%	62,468

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.Pro505=
Coding: c.1515C>T
MANE Select: NM_001354604
dbSNP: rs761127025
Type: single nucleotide variant
Location: chr3:69965182 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 505: the 'disordered' region

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.Pro505Arg Uncertain significance ★ ⚠ same residue
MITF p.Pro505Ser 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
MITF c.956-1G>A 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-pro505 (accessed [today's date]).

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