Is MITF p.Arg136Gln (c.407G>A) pathogenic?

MITF p.Arg136Gln (c.407G>A) is classified Uncertain significance in MITF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.1645); Ultra-rare (popmax 0.01%, amr); Associated with Tietz syndrome.

What condition is associated with MITF p.Arg136Gln (c.407G>A)?

MITF p.Arg136Gln (c.407G>A) is associated with Tietz syndrome, Waardenburg syndrome type 2A, melanoma, cutaneous malignant, susceptibility to, 8 (ClinVar).

How common is MITF p.Arg136Gln (c.407G>A) in the general population?

MITF p.Arg136Gln (c.407G>A) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about MITF p.Arg136Gln (c.407G>A)?

AlphaMissense predicts likely benign (score 0.1645) — an in-silico prediction, not a clinical call.

MITF p.Arg136Gln

c.407G>A · rs750608171 · VCV1692272

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1645 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Tietz syndrome

Computational evidence

Protein change
AlphaMissense	0.1645	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -5.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 14 kb · p 0.51 · regional, not allelic
Overall
CADD	24.6	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 0.01% Admixed American · 6/59,994 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000991% 16/1,613,920 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,999
Finnishnot grpmax-eligible	0.00468%	21,347
South Asian	0.0011%	91,070
European (non-Finnish)	0.000508%	196,665

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.Arg136Gln
Coding: c.407G>A
MANE Select: NM_001354604
dbSNP: rs750608171
Type: single nucleotide variant
Location: chr3:69937874 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB

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 hereditary neoplastic syndrome

Similar variants

MITF p.Arg136Trp Uncertain significance ★★ ⚠ same residue
MITF p.Arg136= Likely benign ★ 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

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-arg136gln (accessed [today's date]).

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