Is MITF p.Pro498Ala (c.1492C>G) pathogenic?

MITF p.Pro498Ala (c.1492C>G) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-10). AlphaMissense: ambiguous (0.4295); Very rare (popmax 0.00167%, amr); Associated with Tietz syndrome.

What condition is associated with MITF p.Pro498Ala (c.1492C>G)?

MITF p.Pro498Ala (c.1492C>G) is associated with Tietz syndrome, Waardenburg syndrome type 2A, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Pro498Ala (c.1492C>G) in the general population?

MITF p.Pro498Ala (c.1492C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about MITF p.Pro498Ala (c.1492C>G)?

AlphaMissense predicts ambiguous (score 0.4295) — an in-silico prediction, not a clinical call.

MITF p.Pro498Ala

c.1492C>G · rs1414338937 · VCV1716465

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4295 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Tietz syndrome

Computational evidence

Protein change
AlphaMissense	0.4295	ambiguous
REVEL	0.54	indeterminate
SaProt	LLR -6.03	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,907 bp · p 0.32 · regional, not allelic
Overall
CADD	24.9	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 0.00167% Admixed American · 1/60,004 alleles

Overall 6.84e-05% 1/1,461,720 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.Pro498Ala
Coding: c.1492C>G
MANE Select: NM_001354604
dbSNP: rs1414338937
Type: single nucleotide variant
Location: chr3:69965159 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 498: 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.Pro498Leu Uncertain significance ★★ ⚠ same residue
MITF p.Pro498= Likely benign ★★ 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-pro498ala (accessed [today's date]).

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