Is MITF p.Arg362Ter (c.1084C>T) pathogenic?

MITF p.Arg362Ter (c.1084C>T) is classified Pathogenic/Likely pathogenic in MITF (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-10). Very rare (popmax 0.0011%, sas); Associated with Waardenburg syndrome type 2A.

What condition is associated with MITF p.Arg362Ter (c.1084C>T)?

MITF p.Arg362Ter (c.1084C>T) is associated with Waardenburg syndrome type 2A, Tietz syndrome, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Arg362Ter (c.1084C>T) in the general population?

MITF p.Arg362Ter (c.1084C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

MITF p.Arg362Ter

c.1084C>T · rs1057517966 · VCV372755

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

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	predicted	premature termination codon in exon 9 of 10
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.31, phastCons 0.98
Overall
CADD	38.0	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

Grpmax group 0.0011% South Asian · 1/91,084 alleles

Overall 6.2e-05% 1/1,614,026 alleles · very rare exomes 1/1,461,810 · genomes 0/152,216 · joint denominator

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.Arg362Ter
Coding: c.1084C>T
MANE Select: NM_001354604
dbSNP: rs1057517966
Type: single nucleotide variant
Location: chr3:69959325 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 362: the bhlh domain; an α-helix

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 hereditary neoplastic syndrome

Similar variants

MITF p.Arg362Gln 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
MITF p.Arg217Ter Pathogenic/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-arg362ter (accessed [today's date]).

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