Is MPZL2 p.Pro129Arg (c.386C>G) pathogenic?

MPZL2 p.Pro129Arg (c.386C>G) is classified Likely pathogenic in MPZL2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-02). AlphaMissense: likely pathogenic (0.922); Rare (popmax 0.135%, amr); Associated with Inborn genetic diseases.

What condition is associated with MPZL2 p.Pro129Arg (c.386C>G)?

MPZL2 p.Pro129Arg (c.386C>G) is associated with Inborn genetic diseases (ClinVar).

How common is MPZL2 p.Pro129Arg (c.386C>G) in the general population?

MPZL2 p.Pro129Arg (c.386C>G) is rare (popmax 0.135%, amr) (gnomAD).

What do computational predictors say about MPZL2 p.Pro129Arg (c.386C>G)?

AlphaMissense predicts likely pathogenic (score 0.922) — an in-silico prediction, not a clinical call.

MPZL2 p.Pro129Arg

c.386C>G · rs773599467 · VCV1216057

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.922 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.135%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.922	likely pathogenic ✓ concordant with ClinVar
REVEL	0.66	pathogenic-leaning
SaProt	LLR -13.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 6,900 bp · p 0.079 · regional, not allelic
Overall
CADD	31.0	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 0.135% Admixed American · 81/60,008 alleles

Filtering AF 0.111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.102%

Overall 0.00508% 82/1,614,006 alleles · rare exomes 76/1,461,840 · genomes 6/152,166 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.135%	741
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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: MPZL2
Protein: p.Pro129Arg
Coding: c.386C>G
MANE Select: NM_005797
dbSNP: rs773599467
Type: single nucleotide variant
Location: chr11:118262488 (GRCh38)
Gene constraint: LOEUF 1.703 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.54
Residue 129: a UniProt-annotated variant site (in dfnb111; pathogenic); the ig-like v-type domain

Full MPZL2 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

MPZL2 p.Arg103Gln Uncertain significance ★★ ⚠ same condition
MPZL2 p.Arg33Gln Uncertain significance ★★ ⚠ same condition
MPZL2 p.Ile151Thr Uncertain significance ★★ same condition
MPZL2 p.Arg147Cys Uncertain significance ★ ⚠ same condition
MPZL2 p.Arg147His Uncertain significance ★ ⚠ same condition
MPZL2 p.Arg179Trp Uncertain significance ★ ⚠ same condition
MPZL2 p.Arg182Gln Uncertain significance ★ ⚠ same condition
MPZL2 p.Arg200Ser 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/mpzl2-p-pro129arg (accessed [today's date]).

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