Is MITF p.Glu394Asp (c.1182A>T) pathogenic?

MITF p.Glu394Asp (c.1182A>T) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-07). AlphaMissense: likely pathogenic (0.9774); Very rare (popmax 0.00186%, nfe); Associated with coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness.

How common is MITF p.Glu394Asp (c.1182A>T) in the general population?

MITF p.Glu394Asp (c.1182A>T) is very rare (popmax 0.00186%, nfe) (gnomAD).

What do computational predictors say about MITF p.Glu394Asp (c.1182A>T)?

AlphaMissense predicts likely pathogenic (score 0.9774) — an in-silico prediction, not a clinical call.

MITF p.Glu394Asp

Q: What condition is associated with MITF p.Glu394Asp (c.1182A>T)?

MITF p.Glu394Asp (c.1182A>T) is associated with coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness, Tietz syndrome, Waardenburg syndrome type 2A (ClinVar).

c.1182A>T · rs137904015 · VCV2943489

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9774 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness

Computational evidence

Protein change
AlphaMissense	0.9774	likely pathogenic
REVEL	0.125	moderately benign-leaning
SaProt	LLR -10.75	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,907 bp · p 0.32 · regional, not allelic
Overall
CADD	23.6	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 0.00186% European (non-Finnish) · 22/1,179,966 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00143% 23/1,614,032 alleles · very rare exomes 23/1,461,788 · genomes 0/152,244 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00186%	53,635
Remaining individualsnot grpmax-eligible	0.0016%	62,496

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.Glu394Asp
Coding: c.1182A>T
MANE Select: NM_001354604
dbSNP: rs137904015
Type: single nucleotide variant
Location: chr3:69964849 (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

coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Tietz syndrome Waardenburg syndrome type 2A melanoma, cutaneous malignant, susceptibility to, 8 hereditary neoplastic syndrome

Similar variants

MITF p.Glu394= Benign/Likely benign ★★ same residue
MITF p.Glu394Lys 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
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-glu394asp (accessed [today's date]).

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