Is MITF p.Pro498= (c.1494A>C) pathogenic?

MITF p.Pro498= (c.1494A>C) is classified Likely benign in MITF (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-06-01). Ultra-rare (popmax 0.0101%, nfe); Associated with melanoma, cutaneous malignant, susceptibility to, 8.

What condition is associated with MITF p.Pro498= (c.1494A>C)?

MITF p.Pro498= (c.1494A>C) is associated with melanoma, cutaneous malignant, susceptibility to, 8, Tietz syndrome, Waardenburg syndrome type 2A (ClinVar).

How common is MITF p.Pro498= (c.1494A>C) in the general population?

MITF p.Pro498= (c.1494A>C) is ultra-rare (popmax 0.0101%, nfe) (gnomAD).

MITF p.Pro498=

c.1494A>C · rs777982903 · VCV1338052

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0101%, nfe)

Conditions

melanoma, cutaneous malignant, susceptibility to, 8

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 -6.7	GERP -4.3
Overall
CADD	0.202	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0101% European (non-Finnish) · 119/1,179,822 alleles

Filtering AF 0.00859% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00804%

Overall 0.00787% 127/1,613,496 alleles · ultra-rare exomes 119/1,461,672 · genomes 8/151,824 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0101%	9,914
Remaining individualsnot grpmax-eligible	0.00961%	10,410
Admixed American	0.00167%	59,954
African / African-American	0.00134%	74,820

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.Pro498=
Coding: c.1494A>C
MANE Select: NM_001354604
dbSNP: rs777982903
Type: single nucleotide variant
Location: chr3:69965161 (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

melanoma, cutaneous malignant, susceptibility to, 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Tietz syndrome Waardenburg syndrome type 2A hereditary neoplastic syndrome

For MITF-related melanoma and renal cell carcinoma predisposition syndrome (Orphanet):

Onset: Adult, Elderly

Similar variants

MITF p.Pro498Ala Uncertain significance ★★ same residue
MITF p.Pro498Leu 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-pro498 (accessed [today's date]).

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