Is MLPH p.Arg139Trp (c.415C>T) pathogenic?

MLPH p.Arg139Trp (c.415C>T) is classified Benign in MLPH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-23). AlphaMissense: likely benign (0.1925); Low-frequency (popmax 3.78%, sas).

How common is MLPH p.Arg139Trp (c.415C>T) in the general population?

MLPH p.Arg139Trp (c.415C>T) is low-frequency (popmax 3.78%, sas) (gnomAD).

What do computational predictors say about MLPH p.Arg139Trp (c.415C>T)?

AlphaMissense predicts likely benign (score 0.1925) — an in-silico prediction, not a clinical call.

MLPH p.Arg139Trp

c.415C>T · rs2292880 · VCV1601105

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1925 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.78%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1925	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -13.81	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 2.2, phastCons 0.47
Regional constraint	o/e 0.98	unconstrained · MANE · 60 kb · p 0.54 · regional, not allelic
Overall
CADD	26.6	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 3.78% South Asian · 3,445/91,068 alleles

Filtering AF 3.68% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.63%

Overall 0.489% 7,893/1,613,884 alleles · low-frequency exomes 7,097/1,461,642 · genomes 796/152,242 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	3.78%	26
Admixed American	2.5%	40
Finnishnot grpmax-eligible	2.38%	42
East Asian	1.13%	88
Remaining individualsnot grpmax-eligible	0.546%	183
Middle Eastern	0.099%	1,010
African / African-American	0.0466%	2,144
European (non-Finnish)	0.0451%	2,218

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.Arg139Trp
Coding: c.415C>T
MANE Select: NM_024101
dbSNP: rs2292880
Type: single nucleotide variant
Location: chr2:237511071 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58
Residue 139: a UniProt-annotated variant site (in)

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

Similar variants

MLPH p.Arg139= Likely benign ★ same residue
MLPH p.Arg35Gln Pathogenic/Likely pathogenic ★★ same type
MLPH p.Arg35Trp Pathogenic/Likely pathogenic ★★ same type
MLPH p.Ala236Thr Uncertain significance ★★ ⚠ same type
MLPH p.Ala520Ser Uncertain significance ★★ ⚠ same type
MLPH p.Arg375Cys Uncertain significance ★★ ⚠ same type
MLPH p.Arg507Trp Uncertain significance ★★ ⚠ same type
MLPH p.Arg518Gly Uncertain significance ★★ ⚠ same type

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-arg139trp (accessed [today's date]).

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