Is MITF p.Ala294Val (c.881C>T) pathogenic?

MITF p.Ala294Val (c.881C>T) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-10). AlphaMissense: likely benign (0.192); Very rare (popmax 0.00534%, afr); Associated with Waardenburg syndrome type 2A.

What condition is associated with MITF p.Ala294Val (c.881C>T)?

MITF p.Ala294Val (c.881C>T) is associated with Waardenburg syndrome type 2A, Tietz syndrome, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Ala294Val (c.881C>T) in the general population?

MITF p.Ala294Val (c.881C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about MITF p.Ala294Val (c.881C>T)?

AlphaMissense predicts likely benign (score 0.192) — an in-silico prediction, not a clinical call.

MITF p.Ala294Val

c.881C>T · rs373945151 · VCV1314112

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.192 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Waardenburg syndrome type 2A

Computational evidence

Protein change
AlphaMissense	0.192	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -9.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP 2.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 14 kb · p 0.51 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,970 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00112% 18/1,612,598 alleles · very rare exomes 14/1,460,358 · genomes 4/152,240 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,742
Remaining individualsnot grpmax-eligible	0.0032%	31,213
East Asian	0.00223%	44,756
South Asian	0.0022%	45,520
Finnishnot grpmax-eligible	0.00156%	63,970
European (non-Finnish)	0.000679%	147,365

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.Ala294Val
Coding: c.881C>T
MANE Select: NM_001354604
dbSNP: rs373945151
Type: single nucleotide variant
Location: chr3:69951812 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 294: a UniProt-annotated variant site (in ws2a; uncertain significance); the 'transactivation' region

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

Disease context

Waardenburg syndrome type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Tietz syndrome melanoma, cutaneous malignant, susceptibility to, 8 coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness hereditary neoplastic syndrome

Similar variants

MITF p.Ala294Glu Uncertain significance ★★ ⚠ same residue
MITF p.Ala294= Likely benign ★★ same residue
MITF p.Ala294fs Likely pathogenic ★ 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

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-ala294val (accessed [today's date]).

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