Is MITF p.Pro339= (c.1017C>A) pathogenic?

MITF p.Pro339= (c.1017C>A) is classified Likely benign in MITF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-05). Very rare (popmax 0.000255%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MITF p.Pro339= (c.1017C>A)?

MITF p.Pro339= (c.1017C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MITF p.Pro339= (c.1017C>A) in the general population?

MITF p.Pro339= (c.1017C>A) is very rare (popmax 0.000255%, nfe) (gnomAD).

MITF p.Pro339=

c.1017C>A · VCV3873258

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

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 2.3	GERP 1.3, phastCons 1
Overall
CADD	12.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000255% European (non-Finnish) · 3/1,178,488 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,460,100 alleles · very rare

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.Pro339=
Coding: c.1017C>A
MANE Select: NM_001354604
Type: single nucleotide variant
Location: chr3:69956516 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 339: the bhlh domain

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

Similar variants

MITF p.Arg362Ter Pathogenic/Likely pathogenic ★★ same condition
MITF c.881-9C>G Uncertain significance ★★ same condition
MITF p.Ala148Thr Uncertain significance ★★ ⚠ same condition
MITF p.Ala152Thr Uncertain significance ★★ ⚠ same condition
MITF p.Ala177Thr Uncertain significance ★★ ⚠ same condition
MITF p.Ala183Ser Uncertain significance ★★ ⚠ same condition
MITF p.Ala205Thr Uncertain significance ★★ ⚠ same condition
MITF p.Ala252Thr Uncertain significance ★★ ⚠ 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-pro339 (accessed [today's date]).

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