Is ALG12 p.Arg146Gln (c.437G>A) pathogenic?

ALG12 p.Arg146Gln (c.437G>A) is classified Pathogenic/Likely pathogenic in ALG12 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-11-06). AlphaMissense: likely pathogenic (0.6137); Ultra-rare (popmax 0.0139%, nfe); Associated with ALG12-related disorder.

What condition is associated with ALG12 p.Arg146Gln (c.437G>A)?

ALG12 p.Arg146Gln (c.437G>A) is associated with ALG12-related disorder, ALG12-congenital disorder of glycosylation (ClinVar).

How common is ALG12 p.Arg146Gln (c.437G>A) in the general population?

ALG12 p.Arg146Gln (c.437G>A) is ultra-rare (popmax 0.0139%, nfe) (gnomAD).

What do computational predictors say about ALG12 p.Arg146Gln (c.437G>A)?

AlphaMissense predicts likely pathogenic (score 0.6137) — an in-silico prediction, not a clinical call.

ALG12 p.Arg146Gln

c.437G>A · rs121907932 · VCV3435

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.6137 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0139%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG12-related disorder

Computational evidence

Protein change
AlphaMissense	0.6137	likely pathogenic ✓ concordant with ClinVar
REVEL	0.772	pathogenic-leaning
SaProt	LLR -14.56	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 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 9,924 bp · p 0.17 · regional, not allelic
Overall
CADD	32.0	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 0.0139% European (non-Finnish) · 164/1,180,028 alleles

Filtering AF 0.0121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0115%

Overall 0.0123% 199/1,613,640 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0224%	4,462
European (non-Finnish)grpmax	0.0139%	7,195
Admixed American	0.0117%	8,571
Finnishnot grpmax-eligible	0.011%	9,087
African / African-American	0.00667%	14,989
South Asian	0.0022%	45,545

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: ALG12
Protein: p.Arg146Gln
Coding: c.437G>A
MANE Select: NM_024105
dbSNP: rs121907932
Type: single nucleotide variant
Location: chr22:49910466 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.26
Residue 146: a UniProt-annotated variant site (in cdg1g; loss of function in dolichol-linked oligosaccharide biosynthetic process)

Full ALG12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG12-related disorder

Also linked: ALG12-congenital disorder of glycosylation

Similar variants

ALG12 p.Arg146Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
ALG12 p.Arg146= Likely benign ★ same residue
ALG12 c.295+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALG12 c.768+1G>A Likely pathogenic ★★ same condition
ALG12 p.Arg202Ter Pathogenic/Likely pathogenic ★★ same condition
ALG12 p.Gly101Arg Likely pathogenic ★★ same condition
ALG12 p.Thr67Met Pathogenic/Likely pathogenic ★★ same condition
ALG12 c.469+5G>A 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/alg12-p-arg146gln (accessed [today's date]).

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