Is MLPH p.Arg507Trp (c.1519C>T) pathogenic?

MLPH p.Arg507Trp (c.1519C>T) is classified Uncertain significance in MLPH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-17). AlphaMissense: likely benign (0.155); Ultra-rare (popmax 0.0125%, amr); Associated with Inborn genetic diseases.

What condition is associated with MLPH p.Arg507Trp (c.1519C>T)?

MLPH p.Arg507Trp (c.1519C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MLPH p.Arg507Trp (c.1519C>T) in the general population?

MLPH p.Arg507Trp (c.1519C>T) is ultra-rare (popmax 0.0125%, amr) (gnomAD).

What do computational predictors say about MLPH p.Arg507Trp (c.1519C>T)?

AlphaMissense predicts likely benign (score 0.155) — an in-silico prediction, not a clinical call.

MLPH p.Arg507Trp

c.1519C>T · rs143701698 · VCV2561153

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.155 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.155	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -9.50	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 0.97	GERP 1.9
Regional constraint	o/e 0.98	unconstrained · MANE · 60 kb · p 0.54 · regional, not allelic
Overall
CADD	22.0	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 0.0125% Admixed American · 7/56,152 alleles

Filtering AF 0.0079% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00838% 133/1,587,984 alleles · ultra-rare exomes 123/1,436,714 · genomes 10/151,270 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0125%	8,022
European (non-Finnish)	0.00933%	10,718
South Asian	0.00687%	14,556
Remaining individualsnot grpmax-eligible	0.0065%	15,387
African / African-American	0.00538%	18,577
Ashkenazi Jewishnot grpmax-eligible	0.00344%	29,096
Finnishnot grpmax-eligible	0.00329%	30,355

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.Arg507Trp
Coding: c.1519C>T
MANE Select: NM_024101
dbSNP: rs143701698
Type: single nucleotide variant
Location: chr2:237542639 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58
Residue 507: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MLPH p.Arg507Gln Uncertain significance ★ ⚠ same residue
MLPH p.Arg507= Likely benign ★ same residue
MLPH p.Ala520Ser Uncertain significance ★★ ⚠ same condition
MLPH p.Arg375Cys Uncertain significance ★★ ⚠ same condition
MLPH p.Arg518Gly Uncertain significance ★★ ⚠ same condition
MLPH p.Asp194Asn Uncertain significance ★★ ⚠ same condition
MLPH p.Asp310Asn Uncertain significance ★★ ⚠ same condition
MLPH p.Gln208His Uncertain significance ★★ ⚠ 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-arg507trp (accessed [today's date]).

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