Is MITF p.Arg322= (c.966A>G) pathogenic?

MITF p.Arg322= (c.966A>G) is classified Likely benign in MITF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). Ultra-rare (popmax 0.033%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with MITF p.Arg322= (c.966A>G)?

MITF p.Arg322= (c.966A>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MITF p.Arg322= (c.966A>G) in the general population?

MITF p.Arg322= (c.966A>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

MITF p.Arg322=

c.966A>G · VCV4108288

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP -1.6, phastCons 1
Overall
CADD	12.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,056 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000124% 2/1,613,456 alleles · ultra-rare exomes 2/1,461,114 · genomes 0/152,342 · 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.Arg322=
Coding: c.966A>G
MANE Select: NM_001354604
Type: single nucleotide variant
Location: chr3:69956465 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 322: the bhlh domain

Full MITF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MITF p.Arg322Lys Uncertain significance ★★ ⚠ same residue
MITF p.Arg322Gly Uncertain significance ★ ⚠ same residue
MITF p.Arg362Ter Pathogenic/Likely pathogenic ★★ same condition
MITF c.881-9C>G Uncertain significance ★★ same condition
MITF p.Ala148Thr Uncertain significance ★★ ⚠ same condition
MITF p.Ala152Thr Uncertain significance ★★ ⚠ same condition
MITF p.Ala177Thr Uncertain significance ★★ ⚠ same condition
MITF p.Ala183Ser Uncertain significance ★★ ⚠ 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-arg322 (accessed [today's date]).

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