Is VMA12 p.Arg31Pro (c.92G>C) pathogenic?

VMA12 p.Arg31Pro (c.92G>C) is classified Pathogenic/Likely pathogenic in VMA12 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-08-12). AlphaMissense: likely pathogenic (0.5867); Very rare (popmax 0.00833%, amr); Associated with TMEM199-related disorder.

What condition is associated with VMA12 p.Arg31Pro (c.92G>C)?

VMA12 p.Arg31Pro (c.92G>C) is associated with TMEM199-related disorder, TMEM199-CDG (ClinVar).

How common is VMA12 p.Arg31Pro (c.92G>C) in the general population?

VMA12 p.Arg31Pro (c.92G>C) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about VMA12 p.Arg31Pro (c.92G>C)?

AlphaMissense predicts likely pathogenic (score 0.5867) — an in-silico prediction, not a clinical call.

VMA12 p.Arg31Pro

c.92G>C · rs782531869 · VCV218964

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.5867 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TMEM199-related disorder

Computational evidence

Protein change
AlphaMissense	0.5867	likely pathogenic ✓ concordant with ClinVar
REVEL	0.182	moderately benign-leaning
SaProt	LLR -14.19	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 3,578 bp · p 0.26 · regional, not allelic
Overall
CADD	23.1	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 0.00833% Admixed American · 5/60,002 alleles

Filtering AF 0.00511% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00527% 85/1,613,342 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,000
European (non-Finnish)	0.00627%	15,946
South Asian	0.00439%	22,772
Remaining individualsnot grpmax-eligible	0.0032%	31,238

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: VMA12
Protein: p.Arg31Pro
Coding: c.92G>C
MANE Select: NM_152464
dbSNP: rs782531869
Type: single nucleotide variant
Location: chr17:28357762 (GRCh38)
Structure: AlphaFold pLDDT 80.82
Residue 31: a UniProt-annotated variant site (in cdg2p)

Full VMA12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

TMEM199-related disorder

Also linked: TMEM199-CDG

Similar variants

VMA12 p.Ala7Glu Likely pathogenic ★ ⚠ same condition
VMA12 c.376-1G>A Pathogenic same condition
VMA12 p.Ala14Pro Pathogenic ⚠ same condition
VMA12 c.-7del Likely benign same condition
VMA12 p.Ala7Thr Uncertain significance ★★ ⚠ same type
VMA12 p.Arg120His Uncertain significance ★★ ⚠ same type
VMA12 p.Arg178Trp Uncertain significance ★★ ⚠ same type
VMA12 p.Arg199Gly 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/vma12-p-arg31pro (accessed [today's date]).

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