Is MITF p.Glu466Lys (c.1396G>A) pathogenic?

MITF p.Glu466Lys (c.1396G>A) is classified Conflicting classifications of pathogenicity in MITF (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-31). AlphaMissense: likely benign (0.1159); Ultra-rare (popmax 0.066%, mid); Associated with Waardenburg syndrome type 2A.

What condition is associated with MITF p.Glu466Lys (c.1396G>A)?

MITF p.Glu466Lys (c.1396G>A) is associated with Waardenburg syndrome type 2A, Tietz syndrome, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Glu466Lys (c.1396G>A) in the general population?

MITF p.Glu466Lys (c.1396G>A) is ultra-rare (popmax 0.066%, mid) (gnomAD).

What do computational predictors say about MITF p.Glu466Lys (c.1396G>A)?

AlphaMissense predicts likely benign (score 0.1159) — an in-silico prediction, not a clinical call.

MITF p.Glu466Lys

c.1396G>A · rs150995386 · VCV900477

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1159 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Waardenburg syndrome type 2A

Computational evidence

Protein change
AlphaMissense	0.1159	likely benign
REVEL	0.263	benign-leaning
SaProt	LLR -6.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this 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	22.2	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 0.066% Middle Eastern · 4/6,062 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00328% 53/1,614,120 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.0112%	8,929
South Asian	0.00439%	22,771
European (non-Finnish)	0.00314%	31,893
Admixed American	0.00167%	60,010

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.Glu466Lys
Coding: c.1396G>A
MANE Select: NM_001354604
dbSNP: rs150995386
Type: single nucleotide variant
Location: chr3:69965063 (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

Waardenburg syndrome type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Tietz syndrome melanoma, cutaneous malignant, susceptibility to, 8

Similar variants

MITF p.Glu466Gln Uncertain significance ★★ ⚠ same residue
MITF p.Glu466= 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-glu466lys (accessed [today's date]).

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