Is MLPH p.Glu407= (c.1221A>G) pathogenic?

MLPH p.Glu407= (c.1221A>G) is classified Benign in MLPH (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). Common (popmax 82.2%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Griscelli syndrome type 3.

What condition is associated with MLPH p.Glu407= (c.1221A>G)?

MLPH p.Glu407= (c.1221A>G) is associated with Griscelli syndrome type 3 (ClinVar).

How is Griscelli syndrome inherited?

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

MLPH p.Glu407=

Q: How common is MLPH p.Glu407= (c.1221A>G) in the general population?

MLPH p.Glu407= (c.1221A>G) is common (popmax 82.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1221A>G · rs2271809 · VCV1287353

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 82.2%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Griscelli syndrome type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.022	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.16	GERP -1.9
Overall
CADD	1.057	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 82.2% African / African-American · 61,608/74,980 alleles

Filtering AF 81.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 81.4%

Overall 32.6% 526,240/1,612,888 alleles · common exomes 458,856/1,460,744 · genomes 67,384/152,144 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	82.2%	1
South Asian	41.5%	2
East Asian	39.9%	3
Admixed American	35.9%	3
Remaining individualsnot grpmax-eligible	34.9%	3
Middle Eastern	32.7%	3
European (non-Finnish)	28.8%	3
Ashkenazi Jewishnot grpmax-eligible	27.5%	4
Amishnot grpmax-eligible	25.2%	4
Finnishnot grpmax-eligible	24.9%	4

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.Glu407=
Coding: c.1221A>G
MANE Select: NM_024101
dbSNP: rs2271809
Type: single nucleotide variant
Location: chr2:237540464 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58
Residue 407: 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.Glu174= Benign/Likely 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-glu407 (accessed [today's date]).

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