Is MITF p.Pro344Leu (c.1031C>T) pathogenic?

MITF p.Pro344Leu (c.1031C>T) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-28). AlphaMissense: likely pathogenic (0.8536); Rare (popmax 0.116%, mid); Associated with Waardenburg syndrome type 2A.

What condition is associated with MITF p.Pro344Leu (c.1031C>T)?

MITF p.Pro344Leu (c.1031C>T) is associated with Waardenburg syndrome type 2A, Tietz syndrome, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Pro344Leu (c.1031C>T) in the general population?

MITF p.Pro344Leu (c.1031C>T) is rare (popmax 0.116%, mid) (gnomAD).

What do computational predictors say about MITF p.Pro344Leu (c.1031C>T)?

AlphaMissense predicts likely pathogenic (score 0.8536) — an in-silico prediction, not a clinical call.

MITF p.Pro344Leu

c.1031C>T · rs756923654 · VCV800541

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8536 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.116%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Waardenburg syndrome type 2A

Computational evidence

Protein change
AlphaMissense	0.8536	likely pathogenic
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -10.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 7,490 bp · p 4.1e-07 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.116% Middle Eastern · 7/6,060 alleles

Filtering AF 0.0542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0384%

Overall 0.00305% 49/1,607,714 alleles · rare exomes 47/1,455,642 · genomes 2/152,072 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.116%	866
Remaining individualsnot grpmax-eligible	0.00321%	31,127
European (non-Finnish)	0.00315%	31,741
East Asian	0.00223%	44,794
African / African-American	0.00134%	74,762
South Asian	0.0011%	90,964

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.Pro344Leu
Coding: c.1031C>T
MANE Select: NM_001354604
dbSNP: rs756923654
Type: single nucleotide variant
Location: chr3:69956530 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 344: the bhlh domain

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

Similar variants

MITF p.Pro344= Uncertain significance ★ 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
MITF c.956-1G>A Pathogenic ★★ same condition
MITF p.Arg217Ter Pathogenic/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-pro344leu (accessed [today's date]).

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