Is MITF p.Val427Ala (c.1280T>C) pathogenic?

MITF p.Val427Ala (c.1280T>C) is classified Benign/Likely benign in MITF (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0726); Rare (popmax 0.309%, afr); Associated with melanoma, cutaneous malignant, susceptibility to, 8.

What condition is associated with MITF p.Val427Ala (c.1280T>C)?

MITF p.Val427Ala (c.1280T>C) is associated with melanoma, cutaneous malignant, susceptibility to, 8, Tietz syndrome, Waardenburg syndrome type 2A (ClinVar).

How common is MITF p.Val427Ala (c.1280T>C) in the general population?

MITF p.Val427Ala (c.1280T>C) is rare (popmax 0.309%, afr) (gnomAD).

What do computational predictors say about MITF p.Val427Ala (c.1280T>C)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

MITF p.Val427Ala

c.1280T>C · rs2055006 · VCV346499

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.309%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

melanoma, cutaneous malignant, susceptibility to, 8

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.1, phastCons 0.86
Regional constraint	o/e 1.07	unconstrained · MANE · 5,907 bp · p 0.32 · regional, not allelic
Overall
CADD	15.4	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 0.309% African / African-American · 232/75,012 alleles

Filtering AF 0.277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.264%

Overall 0.026% 420/1,614,072 alleles · rare exomes 285/1,461,886 · genomes 135/152,186 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.309%	323
Middle Eastern	0.165%	606
Remaining individualsnot grpmax-eligible	0.0464%	2,155
Admixed American	0.0317%	3,158
European (non-Finnish)	0.0109%	9,147
South Asian	0.0011%	91,080

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.Val427Ala
Coding: c.1280T>C
MANE Select: NM_001354604
dbSNP: rs2055006
Type: single nucleotide variant
Location: chr3:69964947 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 427: the 'dna-binding regulation' region

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.Val427Ile Uncertain significance ★ ⚠ same residue
MITF p.Val427Phe 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

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-val427ala (accessed [today's date]).

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