Is MITF p.Arg366Gln (c.1097G>A) pathogenic?

MITF p.Arg366Gln (c.1097G>A) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-14). AlphaMissense: likely benign (0.2342); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with MITF p.Arg366Gln (c.1097G>A)?

MITF p.Arg366Gln (c.1097G>A) is associated with hereditary neoplastic syndrome, Tietz syndrome, Waardenburg syndrome type 2A (ClinVar).

How common is MITF p.Arg366Gln (c.1097G>A) in the general population?

MITF p.Arg366Gln (c.1097G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about MITF p.Arg366Gln (c.1097G>A)?

AlphaMissense predicts likely benign (score 0.2342) — an in-silico prediction, not a clinical call.

MITF p.Arg366Gln

c.1097G>A · rs762920442 · VCV2288639

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2342 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2342	likely benign
REVEL	0.499	indeterminate
SaProt	LLR -9.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
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	28.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 · 1/44,854 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000372% 6/1,613,870 alleles · very rare exomes 4/1,461,782 · genomes 2/152,088 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,854
Admixed American	0.00167%	59,978
African / African-American	0.00134%	74,888
South Asian	0.0011%	91,076
European (non-Finnish)	0.000169%	589,991

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.Arg366Gln
Coding: c.1097G>A
MANE Select: NM_001354604
dbSNP: rs762920442
Type: single nucleotide variant
Location: chr3:69959338 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 366: an α-helix

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

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

Similar variants

MITF p.Arg366Ter Pathogenic ★★ 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-arg366gln (accessed [today's date]).

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