Is MLPH p.His63Arg (c.188A>G) pathogenic?

MLPH p.His63Arg (c.188A>G) is classified Uncertain significance in MLPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.3171); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MLPH p.His63Arg (c.188A>G)?

MLPH p.His63Arg (c.188A>G) is associated with Inborn genetic diseases (ClinVar).

How common is MLPH p.His63Arg (c.188A>G) in the general population?

MLPH p.His63Arg (c.188A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about MLPH p.His63Arg (c.188A>G)?

AlphaMissense predicts likely benign (score 0.3171) — an in-silico prediction, not a clinical call.

MLPH p.His63Arg

c.188A>G · VCV4055594

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3171 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3171	likely benign
REVEL	0.571	indeterminate
SaProt	LLR -8.19	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP -0.26, phastCons 1
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

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 8.47e-05% European (non-Finnish) · 1/1,180,044 alleles

Overall 6.2e-05% 1/1,613,806 alleles · very rare exomes 1/1,461,430 · genomes 0/152,376 · joint denominator

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.His63Arg
Coding: c.188A>G
MANE Select: NM_024101
Type: single nucleotide variant
Location: chr2:237510651 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58
Residue 63: the rabbd domain

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.Ala520Ser Uncertain significance ★★ ⚠ same condition
MLPH p.Arg375Cys Uncertain significance ★★ ⚠ same condition
MLPH p.Arg507Trp 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
MLPH p.Glu33Lys 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-his63arg (accessed [today's date]).

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