Is ALG12 p.Ser36Arg (c.108C>G) pathogenic?

ALG12 p.Ser36Arg (c.108C>G) is classified Uncertain significance in ALG12 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-02-29). AlphaMissense: likely pathogenic (0.99); Very rare (popmax 0.000254%, nfe); Associated with ALG12-related disorder.

What condition is associated with ALG12 p.Ser36Arg (c.108C>G)?

ALG12 p.Ser36Arg (c.108C>G) is associated with ALG12-related disorder (ClinVar).

How common is ALG12 p.Ser36Arg (c.108C>G) in the general population?

ALG12 p.Ser36Arg (c.108C>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ALG12 p.Ser36Arg (c.108C>G)?

AlphaMissense predicts likely pathogenic (score 0.99) — an in-silico prediction, not a clinical call.

ALG12 p.Ser36Arg

c.108C>G · rs2519275612 · VCV3061429

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.99 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG12-related disorder

Computational evidence

Protein change
AlphaMissense	0.99	likely pathogenic · top 1% in ALG12
REVEL	0.885	moderately pathogenic-leaning
SaProt	LLR -17.13	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 5.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 9,924 bp · p 0.17 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000254% European (non-Finnish) · 3/1,180,032 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,461,808 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)grpmax	0.000254%	393,345

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.Ser36Arg
Coding: c.108C>G
MANE Select: NM_024105
dbSNP: rs2519275612
Type: single nucleotide variant
Location: chr22:49913658 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.26

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

Disease context

ALG12-related disorder

Similar variants

ALG12 p.Ser36Ile Uncertain significance ★ ⚠ same residue
ALG12 p.Arg146Gln Pathogenic/Likely pathogenic ★★ same condition
ALG12 p.Gly101Arg Likely pathogenic ★★ same condition
ALG12 p.Leu159= Likely benign same condition
ALG12 c.295+1G>A Pathogenic/Likely pathogenic ★★ same type
ALG12 c.768+1G>A Likely pathogenic ★★ same type
ALG12 p.Arg202Ter Pathogenic/Likely pathogenic ★★ same type
ALG12 p.Thr67Met Pathogenic/Likely pathogenic ★★ 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/alg12-p-ser36arg (accessed [today's date]).

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