Is MITF p.Val139Ile (c.415G>A) pathogenic?

MITF p.Val139Ile (c.415G>A) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-29). AlphaMissense: ambiguous (0.3822); Very rare (popmax 0.00267%, afr); Associated with melanoma, cutaneous malignant, susceptibility to, 8.

What condition is associated with MITF p.Val139Ile (c.415G>A)?

MITF p.Val139Ile (c.415G>A) is associated with melanoma, cutaneous malignant, susceptibility to, 8, Tietz syndrome, Waardenburg syndrome type 2A (ClinVar).

How common is MITF p.Val139Ile (c.415G>A) in the general population?

MITF p.Val139Ile (c.415G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about MITF p.Val139Ile (c.415G>A)?

AlphaMissense predicts ambiguous (score 0.3822) — an in-silico prediction, not a clinical call.

MITF p.Val139Ile

c.415G>A · rs371031432 · VCV1184722

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3822 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

melanoma, cutaneous malignant, susceptibility to, 8

Computational evidence

Protein change
AlphaMissense	0.3822	ambiguous
REVEL	0.255	benign-leaning
SaProt	LLR -5.64	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.86	donor loss, 1 bp away · masked 0 · deltas
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	32.0	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 0.00267% African / African-American · 2/74,902 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00118% 19/1,613,944 alleles · very rare exomes 14/1,461,818 · genomes 5/152,126 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,451
European (non-Finnish)	0.00144%	69,412

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.Val139Ile
Coding: c.415G>A
MANE Select: NM_001354604
dbSNP: rs371031432
Type: single nucleotide variant
Location: chr3:69937882 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB

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

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

Onset: Adult, Elderly

Similar variants

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
MITF p.Arg310Gly 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-val139ile (accessed [today's date]).

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