Is MITF p.Asp487Gly (c.1460A>G) pathogenic?

MITF p.Asp487Gly (c.1460A>G) is classified Uncertain significance in MITF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-03). AlphaMissense: ambiguous (0.5508); Absent from gnomAD v4.1; Associated with Tietz syndrome.

What condition is associated with MITF p.Asp487Gly (c.1460A>G)?

MITF p.Asp487Gly (c.1460A>G) is associated with Tietz syndrome, Waardenburg syndrome type 2A, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Asp487Gly (c.1460A>G) in the general population?

MITF p.Asp487Gly (c.1460A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MITF p.Asp487Gly (c.1460A>G)?

AlphaMissense predicts ambiguous (score 0.5508) — an in-silico prediction, not a clinical call.

MITF p.Asp487Gly

c.1460A>G · VCV3755072

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5508 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Tietz syndrome

Computational evidence

Protein change
AlphaMissense	0.5508	ambiguous
REVEL	0.464	indeterminate
SaProt	LLR -6.84	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,907 bp · p 0.32 · regional, not allelic
Overall
CADD	26.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MITF
Protein: p.Asp487Gly
Coding: c.1460A>G
MANE Select: NM_001354604
Type: single nucleotide variant
Location: chr3:69965127 (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.Asp487Asn Uncertain significance ★ same residue
MITF p.Asp487Glu 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-asp487gly (accessed [today's date]).

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