Is MITF p.Ala218= (c.654G>A) pathogenic?

MITF p.Ala218= (c.654G>A) is classified Likely benign in MITF (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-04-01). Ultra-rare (popmax 0.0869%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with MITF p.Ala218= (c.654G>A)?

MITF p.Ala218= (c.654G>A) is associated with hereditary neoplastic syndrome, Tietz syndrome, Waardenburg syndrome type 2A (ClinVar).

How common is MITF p.Ala218= (c.654G>A) in the general population?

MITF p.Ala218= (c.654G>A) is ultra-rare (popmax 0.0869%, eas) (gnomAD).

MITF p.Ala218=

c.654G>A · rs200769309 · VCV1204821

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0869%, eas)

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 -9.4	GERP -4
Overall
CADD	0.441	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0869% East Asian · 39/44,856 alleles

Filtering AF 0.0653% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0578%

Overall 0.0057% 92/1,613,858 alleles · ultra-rare exomes 79/1,461,696 · genomes 13/152,162 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0869%	1,150
Middle Eastern	0.0329%	3,042
Admixed American	0.0217%	4,614
Remaining individualsnot grpmax-eligible	0.0112%	8,926
South Asian	0.00549%	18,214
African / African-American	0.00267%	37,453
European (non-Finnish)	0.00203%	49,164

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.Ala218=
Coding: c.654G>A
MANE Select: NM_001354604
dbSNP: rs200769309
Type: single nucleotide variant
Location: chr3:69939169 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 218: 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.Ala218Val Uncertain significance ★★ ⚠ same residue
MITF p.Ala218Glu Uncertain significance ★ ⚠ same residue
MITF p.Ala218Thr 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

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-ala218 (accessed [today's date]).

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