MITF p.Glu425Ter
c.1273G>T · rs149617956 · VCV995924
Pathogenic
Single submitter
Classification
Pathogenic
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
Consequence
nonsense (stop-gain)
predicted LoF
gnomAD v4.1
Absent
absent from gnomAD v4.1
Conditions
1
Waardenburg syndrome type 2A
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | nonsense (stop-gain) | predicted loss-of-function in a haploinsufficient gene (ClinGen) |
|---|---|---|
| NMD | escapes | premature termination codon in the last exon (10 of 10) — the truncated protein is likely expressed. PVS1 input, not an applied code |
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 2.1, phastCons 1 |
| Overall | ||
| CADD | 41.0 | PHRED · no single calibrated threshold — expert panels disagree |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
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.Glu425Ter
- Coding
- c.1273G>T
- MANE Select
- NM_001354604
- dbSNP
- rs149617956
- Type
- single nucleotide variant
- Location
- chr3:69964940 (GRCh38)
- Gene constraint
- LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 62.25 · 12 PDB
- Residue 425
- a UniProt-annotated variant site (risk factor for cmm8; risk factor for pheochromocytomas and paragangliomas; results in impaired sumoylation); the 'dna-binding regulation' region
Similar variants
- 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
- MITF p.Arg217Ter Pathogenic/Likely pathogenic ★★ same condition
- MITF p.Arg310Gly 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-glu425ter (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown