Is MITF p.Asp228Asn (c.682G>A) pathogenic?

MITF p.Asp228Asn (c.682G>A) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-12). AlphaMissense: likely pathogenic (0.618); Very rare (popmax 0.0066%, sas); Associated with melanoma, cutaneous malignant, susceptibility to, 8.

What condition is associated with MITF p.Asp228Asn (c.682G>A)?

MITF p.Asp228Asn (c.682G>A) is associated with melanoma, cutaneous malignant, susceptibility to, 8, Tietz syndrome, Waardenburg syndrome type 2A (ClinVar).

How common is MITF p.Asp228Asn (c.682G>A) in the general population?

MITF p.Asp228Asn (c.682G>A) is very rare (popmax 0.0066%, sas) (gnomAD).

What do computational predictors say about MITF p.Asp228Asn (c.682G>A)?

AlphaMissense predicts likely pathogenic (score 0.618) — an in-silico prediction, not a clinical call.

MITF p.Asp228Asn

c.682G>A · rs765051386 · VCV1723701

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.618 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0066%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

melanoma, cutaneous malignant, susceptibility to, 8

Computational evidence

Protein change
AlphaMissense	0.618	likely pathogenic
REVEL	0.417	indeterminate
SaProt	LLR -8.00	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
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 0.96	unconstrained · MANE · 14 kb · p 0.51 · regional, not allelic
Overall
CADD	33.0	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 0.0066% South Asian · 6/90,908 alleles

Filtering AF 0.00287% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000745% 12/1,610,224 alleles · very rare exomes 10/1,458,210 · genomes 2/152,014 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0066%	15,151
Admixed American	0.00334%	29,963
East Asian	0.00224%	44,738
European (non-Finnish)	0.000255%	392,369

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.Asp228Asn
Coding: c.682G>A
MANE Select: NM_001354604
dbSNP: rs765051386
Type: single nucleotide variant
Location: chr3:69941251 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 228: the 'transactivation' region; an α-helix

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

Disease context

melanoma, cutaneous malignant, susceptibility to, 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Tietz syndrome Waardenburg syndrome type 2A hereditary neoplastic syndrome

For MITF-related melanoma and renal cell carcinoma predisposition syndrome (Orphanet):

Onset: Adult, Elderly

Similar variants

MITF p.Asp228Gly Uncertain significance ★ ⚠ same residue
MITF p.Asp228= Likely benign ★ 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-asp228asn (accessed [today's date]).

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