Is MITF p.Glu394Lys (c.1180G>A) pathogenic?

MITF p.Glu394Lys (c.1180G>A) is classified Uncertain significance in MITF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-15). AlphaMissense: likely pathogenic (0.9893); Very rare (popmax 0.00223%, eas); Associated with Tietz syndrome.

What condition is associated with MITF p.Glu394Lys (c.1180G>A)?

MITF p.Glu394Lys (c.1180G>A) is associated with Tietz syndrome, Waardenburg syndrome type 2A, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Glu394Lys (c.1180G>A) in the general population?

MITF p.Glu394Lys (c.1180G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about MITF p.Glu394Lys (c.1180G>A)?

AlphaMissense predicts likely pathogenic (score 0.9893) — an in-silico prediction, not a clinical call.

MITF p.Glu394Lys

c.1180G>A · rs148242520 · VCV2939207

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Tietz syndrome

Computational evidence

Protein change
AlphaMissense	0.9893	likely pathogenic
REVEL	0.522	indeterminate
SaProt	LLR -13.13	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.53 · evaluated, not missing
Pangolin	Δ0.39	loss · gain 0.00 · SpliceAI below 0.2 · independent
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	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,874 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,613,774 alleles · very rare exomes 5/1,461,758 · genomes 1/152,016 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,874
European (non-Finnish)	0.000424%	235,988

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.Glu394Lys
Coding: c.1180G>A
MANE Select: NM_001354604
dbSNP: rs148242520
Type: single nucleotide variant
Location: chr3:69964847 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 394: the 'leucine-zipper' region; an α-helix

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.Glu394Asp Uncertain significance ★★ ⚠ same residue
MITF p.Glu394= Benign/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-glu394lys (accessed [today's date]).

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