Is MLPH p.Arg35Trp (c.103C>T) pathogenic?

MLPH p.Arg35Trp (c.103C>T) is classified Pathogenic/Likely pathogenic in MLPH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-04). AlphaMissense: ambiguous (0.5533); Ultra-rare (popmax 0.0111%, eas); Associated with MLPH-related disorder.

What condition is associated with MLPH p.Arg35Trp (c.103C>T)?

MLPH p.Arg35Trp (c.103C>T) is associated with MLPH-related disorder, Griscelli syndrome type 3 (ClinVar).

How common is MLPH p.Arg35Trp (c.103C>T) in the general population?

MLPH p.Arg35Trp (c.103C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about MLPH p.Arg35Trp (c.103C>T)?

AlphaMissense predicts ambiguous (score 0.5533) — an in-silico prediction, not a clinical call.

MLPH p.Arg35Trp

c.103C>T · rs119473031 · VCV4268

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5533 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Conditions

MLPH-related disorder

Computational evidence

Protein change
AlphaMissense	0.5533	ambiguous
REVEL	0.623	indeterminate
SaProt	LLR -14.15	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -4.7, phastCons 0.7
Regional constraint	o/e 0.98	unconstrained · MANE · 60 kb · p 0.54 · regional, not allelic
Overall
CADD	22.2	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 0.0111% East Asian · 5/44,876 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00124% 20/1,612,816 alleles · ultra-rare exomes 19/1,460,644 · genomes 1/152,172 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,975
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590
Admixed American	0.00333%	29,986
Remaining individualsnot grpmax-eligible	0.0016%	62,390
Finnishnot grpmax-eligible	0.00156%	63,970
South Asian	0.0011%	91,060
European (non-Finnish)	0.000763%	131,008

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.Arg35Trp
Coding: c.103C>T
MANE Select: NM_024101
dbSNP: rs119473031
Type: single nucleotide variant
Location: chr2:237493529 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58
Residue 35: the rabbd domain; a UniProt-annotated variant site (in gs3; abolishes rab27a binding)

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

Disease context

MLPH-related disorder

Also linked: Griscelli syndrome type 3

Similar variants

MLPH p.Arg35Gln Pathogenic/Likely pathogenic ★★ same residue
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
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-arg35trp (accessed [today's date]).

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