Is MITF p.Ser36Arg (c.108T>G) pathogenic?

MITF p.Ser36Arg (c.108T>G) is classified Uncertain significance in MITF (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-18). AlphaMissense: ambiguous (0.3664); Very rare (popmax 0.00133%, afr); Associated with MITF-related disorder.

What condition is associated with MITF p.Ser36Arg (c.108T>G)?

MITF p.Ser36Arg (c.108T>G) is associated with MITF-related disorder (ClinVar).

How common is MITF p.Ser36Arg (c.108T>G) in the general population?

MITF p.Ser36Arg (c.108T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about MITF p.Ser36Arg (c.108T>G)?

AlphaMissense predicts ambiguous (score 0.3664) — an in-silico prediction, not a clinical call.

MITF p.Ser36Arg

c.108T>G · rs1231587306 · VCV2631029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3664 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

MITF-related disorder

Computational evidence

Protein change
AlphaMissense	0.3664	ambiguous
REVEL	0.1	moderately benign-leaning
SaProt	LLR -8.25	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 2.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 140 kb · p 0.48 · regional, not allelic
Overall
CADD	21.3	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 0.00133% African / African-American · 1/74,936 alleles

Overall 6.2e-05% 1/1,614,066 alleles · very rare exomes 0/1,461,844 · genomes 1/152,222 · 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.Ser36Arg
Coding: c.108T>G
MANE Select: NM_001354604
dbSNP: rs1231587306
Type: single nucleotide variant
Location: chr3:69879137 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 36: the 'disordered' region

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

Disease context

MITF-related disorder

Similar variants

MITF p.Arg321Ter Pathogenic ★★ same condition
MITF p.Gly351Glu Likely pathogenic ★★ same condition
MITF p.Cys295Tyr Uncertain significance ★★ ⚠ same condition
MITF p.Gly174Arg Uncertain significance ★★ ⚠ same condition
MITF p.Lys150Asn Uncertain significance ★★ ⚠ same condition
MITF c.1031+1G>T Likely pathogenic ★ same condition
MITF c.1032-2A>G Pathogenic ★ same condition
MITF c.33+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-ser36arg (accessed [today's date]).

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