Is MLPH p.Arg111= (c.333A>G) pathogenic?

MLPH p.Arg111= (c.333A>G) is classified Likely benign in MLPH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-20). Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MLPH p.Arg111= (c.333A>G)?

MLPH p.Arg111= (c.333A>G) is associated with Inborn genetic diseases (ClinVar).

How common is MLPH p.Arg111= (c.333A>G) in the general population?

MLPH p.Arg111= (c.333A>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

MLPH p.Arg111=

c.333A>G · VCV3873606

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.024	GERP -3.8, phastCons 0.12
Overall
CADD	4.118	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,802 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,400 alleles · very rare exomes 2/1,461,514 · genomes 1/151,886 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,468
European (non-Finnish)grpmax	0.00017%	589,901

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg111=
Coding: c.333A>G
MANE Select: NM_024101
Type: single nucleotide variant
Location: chr2:237510989 (GRCh38)
Gene constraint: LOEUF 0.856 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.58
Residue 111: 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-arg111 (accessed [today's date]).

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