Is MLPH p.Val374Ala (c.1121T>C) pathogenic?

MLPH p.Val374Ala (c.1121T>C) is classified Benign in MLPH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0812); Common (popmax 73.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Griscelli syndrome type 3.

What condition is associated with MLPH p.Val374Ala (c.1121T>C)?

MLPH p.Val374Ala (c.1121T>C) 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.

What do computational predictors say about MLPH p.Val374Ala (c.1121T>C)?

AlphaMissense predicts likely benign (score 0.0812) — an in-silico prediction, not a clinical call.

MLPH p.Val374Ala

Q: How common is MLPH p.Val374Ala (c.1121T>C) in the general population?

MLPH p.Val374Ala (c.1121T>C) is common (popmax 73.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1121T>C · rs3817362 · VCV1321173

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0812 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 73.1%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Griscelli syndrome type 3

Computational evidence

Protein change
AlphaMissense	0.0812	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -6.46	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 -0.2	GERP -3.8
Regional constraint	o/e 0.98	unconstrained · MANE · 60 kb · p 0.54 · regional, not allelic
Overall
CADD	0.152	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 73.1% African / African-American · 54,755/74,934 alleles

Filtering AF 72.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 72.3%

Overall 18.7% 301,934/1,612,428 alleles · common exomes 252,186/1,460,422 · genomes 49,748/152,006 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	73.1%	1
East Asian	39.4%	3
South Asian	33.2%	3
Admixed American	30.7%	3
Middle Eastern	26%	4
Remaining individualsnot grpmax-eligible	21.9%	5
Amishnot grpmax-eligible	17.5%	6
Ashkenazi Jewishnot grpmax-eligible	16.9%	6
European (non-Finnish)	12.9%	8
Finnishnot grpmax-eligible	12.4%	8

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.Val374Ala
Coding: c.1121T>C
MANE Select: NM_024101
dbSNP: rs3817362
Type: single nucleotide variant
Location: chr2:237540364 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58
Residue 374: a UniProt-annotated variant site (in)

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 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-val374ala (accessed [today's date]).

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