Is MLPH p.Glu174= (c.522G>A) pathogenic?

MLPH p.Glu174= (c.522G>A) is classified Benign/Likely benign in MLPH (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-07). Low-frequency (popmax 1.15%, amr); Associated with Griscelli syndrome type 3.

What condition is associated with MLPH p.Glu174= (c.522G>A)?

MLPH p.Glu174= (c.522G>A) is associated with Griscelli syndrome type 3 (ClinVar).

How common is MLPH p.Glu174= (c.522G>A) in the general population?

MLPH p.Glu174= (c.522G>A) is low-frequency (popmax 1.15%, amr) (gnomAD).

How is Griscelli syndrome inherited?

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

MLPH p.Glu174=

c.522G>A · rs181807989 · VCV728022

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.15%, amr)

Conditions

Griscelli syndrome type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.55	GERP -2.6, phastCons 0.9
Overall
CADD	3.428	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.15% Admixed American · 687/59,956 alleles

Filtering AF 1.07% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.05%

Overall 0.0443% 714/1,612,760 alleles · low-frequency exomes 551/1,460,524 · genomes 163/152,236 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	1.15%	87
Remaining individualsnot grpmax-eligible	0.0288%	3,467
African / African-American	0.012%	8,328

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.Glu174=
Coding: c.522G>A
MANE Select: NM_024101
dbSNP: rs181807989
Type: single nucleotide variant
Location: chr2:237518615 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58
Residue 174: the 'disordered' region

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.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
MLPH p.Arg24Ter Conflicting classifications of pathogenicity ★ 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-glu174 (accessed [today's date]).

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