Is MLPH p.Arg320Gln (c.959G>A) pathogenic?

MLPH p.Arg320Gln (c.959G>A) is classified Uncertain significance in MLPH (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.0699); Ultra-rare (popmax 0.0165%, mid); Associated with Griscelli syndrome type 3.

What condition is associated with MLPH p.Arg320Gln (c.959G>A)?

MLPH p.Arg320Gln (c.959G>A) is associated with Griscelli syndrome type 3 (ClinVar).

How common is MLPH p.Arg320Gln (c.959G>A) in the general population?

MLPH p.Arg320Gln (c.959G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Griscelli syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MLPH p.Arg320Gln (c.959G>A)?

AlphaMissense predicts likely benign (score 0.0699) — an in-silico prediction, not a clinical call.

MLPH p.Arg320Gln

c.959G>A · rs1353818050 · VCV3250415

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0699 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Griscelli syndrome type 3

Computational evidence

Protein change
AlphaMissense	0.0699	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -5.97	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 -1.6	GERP -4.2
Regional constraint	o/e 0.98	unconstrained · MANE · 60 kb · p 0.54 · regional, not allelic
Overall
CADD	2.404	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000558% 9/1,614,194 alleles · ultra-rare exomes 9/1,461,888 · genomes 0/152,306 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0016%	62,510
African / African-American	0.00133%	75,046
European (non-Finnish)	0.000508%	196,674

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: MLPH
Protein: p.Arg320Gln
Coding: c.959G>A
MANE Select: NM_024101
dbSNP: rs1353818050
Type: single nucleotide variant
Location: chr2:237527455 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58

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

Disease context

Griscelli syndrome type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Griscelli syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

MLPH p.Arg35Gln Pathogenic/Likely pathogenic ★★ same condition
MLPH p.Arg35Trp Pathogenic/Likely pathogenic ★★ same condition
MLPH p.Arg518Gly Uncertain significance ★★ ⚠ same condition
MLPH p.Glu174= Benign/Likely benign ★★ same condition
MLPH p.Glu407= Benign ★★ same condition
MLPH p.Val374Ala Benign ★★ same condition
MLPH c.332+1G>T Likely pathogenic ★ same condition
MLPH p.Ser503Ter 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/mlph-p-arg320gln (accessed [today's date]).

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