Is MITF p.Arg513Gln (c.1538G>A) pathogenic?

MITF p.Arg513Gln (c.1538G>A) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-26). AlphaMissense: likely benign (0.1792); Very rare (popmax 0.00439%, sas); Associated with Tietz syndrome.

What condition is associated with MITF p.Arg513Gln (c.1538G>A)?

MITF p.Arg513Gln (c.1538G>A) is associated with Tietz syndrome, Waardenburg syndrome type 2A, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Arg513Gln (c.1538G>A) in the general population?

MITF p.Arg513Gln (c.1538G>A) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about MITF p.Arg513Gln (c.1538G>A)?

AlphaMissense predicts likely benign (score 0.1792) — an in-silico prediction, not a clinical call.

MITF p.Arg513Gln

c.1538G>A · rs1018390529 · VCV452346

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1792 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Tietz syndrome

Computational evidence

Protein change
AlphaMissense	0.1792	likely benign
REVEL	0.357	indeterminate
SaProt	LLR -7.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 5,907 bp · p 0.32 · regional, not allelic
Overall
CADD	33.0	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 0.00439% South Asian · 4/91,078 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000434% 7/1,613,784 alleles · very rare exomes 7/1,461,526 · genomes 0/152,258 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,769
Remaining individualsnot grpmax-eligible	0.0016%	62,490
Finnishnot grpmax-eligible	0.00156%	64,018
European (non-Finnish)	8.48e-05%	1,179,727

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.Arg513Gln
Coding: c.1538G>A
MANE Select: NM_001354604
dbSNP: rs1018390529
Type: single nucleotide variant
Location: chr3:69965205 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 513: the 'disordered' region

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

Disease context

Tietz syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Waardenburg syndrome type 2A melanoma, cutaneous malignant, susceptibility to, 8

Similar variants

MITF p.Arg513= Likely benign ★★ same residue
MITF p.Arg513Gly Uncertain significance ★ same residue
MITF p.Arg513Trp 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

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-arg513gln (accessed [today's date]).

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