Is MITF p.Asp487Asn (c.1459G>A) pathogenic?

MITF p.Asp487Asn (c.1459G>A) is classified Uncertain significance in MITF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-03). AlphaMissense: ambiguous (0.5115); Ultra-rare (popmax 0.0111%, eas); Associated with Tietz syndrome.

What condition is associated with MITF p.Asp487Asn (c.1459G>A)?

MITF p.Asp487Asn (c.1459G>A) is associated with Tietz syndrome, Waardenburg syndrome type 2A, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Asp487Asn (c.1459G>A) in the general population?

MITF p.Asp487Asn (c.1459G>A) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about MITF p.Asp487Asn (c.1459G>A)?

AlphaMissense predicts ambiguous (score 0.5115) — an in-silico prediction, not a clinical call.

MITF p.Asp487Asn

c.1459G>A · VCV3750255

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5115 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Conditions

Tietz syndrome

Computational evidence

Protein change
AlphaMissense	0.5115	ambiguous
REVEL	0.413	indeterminate
SaProt	LLR -7.35	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,907 bp · p 0.32 · regional, not allelic
Overall
CADD	28.0	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 0.0111% East Asian · 5/44,854 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000372% 6/1,614,122 alleles · ultra-rare exomes 6/1,461,878 · genomes 0/152,244 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,971
South Asian	0.0011%	91,080

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.Asp487Asn
Coding: c.1459G>A
MANE Select: NM_001354604
Type: single nucleotide variant
Location: chr3:69965126 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB

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

Similar variants

MITF p.Asp487= Likely benign ★★ same residue
MITF p.Asp487Glu Uncertain significance ★ ⚠ same residue
MITF p.Asp487Gly 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-asp487asn (accessed [today's date]).

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