Is MITF p.Ala252Glu (c.755C>A) pathogenic?

MITF p.Ala252Glu (c.755C>A) is classified Uncertain significance in MITF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-24). AlphaMissense: likely pathogenic (0.6811); Very rare (popmax 8.52e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MITF p.Ala252Glu (c.755C>A)?

MITF p.Ala252Glu (c.755C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MITF p.Ala252Glu (c.755C>A) in the general population?

MITF p.Ala252Glu (c.755C>A) is very rare (popmax 8.52e-05%, nfe) (gnomAD).

What do computational predictors say about MITF p.Ala252Glu (c.755C>A)?

AlphaMissense predicts likely pathogenic (score 0.6811) — an in-silico prediction, not a clinical call.

MITF p.Ala252Glu

c.755C>A · VCV4055213

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.52e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.6811	likely pathogenic
REVEL	0.125	moderately benign-leaning
SaProt	LLR -7.39	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ1.00 · evaluated, not missing
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	26.5	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

Grpmax group 8.52e-05% European (non-Finnish) · 1/1,173,620 alleles

Overall 6.22e-05% 1/1,606,774 alleles · very rare exomes 1/1,454,554 · genomes 0/152,220 · joint denominator

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.Ala252Glu
Coding: c.755C>A
MANE Select: NM_001354604
Type: single nucleotide variant
Location: chr3:69941324 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 252: the 'transactivation' region

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.Ala252Thr Uncertain significance ★★ ⚠ same residue
MITF p.Ala252Ser Uncertain significance ★ ⚠ same residue
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

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-ala252glu (accessed [today's date]).

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