Is MITF p.Pro282Gln (c.845C>A) pathogenic?

MITF p.Pro282Gln (c.845C>A) is classified Uncertain significance in MITF (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-09-18). AlphaMissense: likely pathogenic (0.9343); Absent from gnomAD v4.1; Associated with MITF-related disorder.

What condition is associated with MITF p.Pro282Gln (c.845C>A)?

MITF p.Pro282Gln (c.845C>A) is associated with MITF-related disorder (ClinVar).

How common is MITF p.Pro282Gln (c.845C>A) in the general population?

MITF p.Pro282Gln (c.845C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MITF p.Pro282Gln (c.845C>A)?

AlphaMissense predicts likely pathogenic (score 0.9343) — an in-silico prediction, not a clinical call.

MITF p.Pro282Gln

c.845C>A · VCV3355851

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9343 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

MITF-related disorder

Computational evidence

Protein change
AlphaMissense	0.9343	likely pathogenic
REVEL	0.373	indeterminate
SaProt	LLR -8.46	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 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 14 kb · p 0.51 · regional, not allelic
Overall
CADD	28.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MITF
Protein: p.Pro282Gln
Coding: c.845C>A
MANE Select: NM_001354604
Type: single nucleotide variant
Location: chr3:69949133 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 282: the 'transactivation' region

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

Disease context

MITF-related disorder

Similar variants

MITF p.Pro282Leu Uncertain significance ★ ⚠ same residue
MITF p.Arg321Ter Pathogenic ★★ same condition
MITF p.Gly351Glu Likely pathogenic ★★ same condition
MITF p.Cys295Tyr Uncertain significance ★★ ⚠ same condition
MITF p.Gly174Arg Uncertain significance ★★ ⚠ same condition
MITF p.Lys150Asn Uncertain significance ★★ ⚠ same condition
MITF c.1031+1G>T Likely pathogenic ★ same condition
MITF c.1032-2A>G 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-pro282gln (accessed [today's date]).

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