Is ALG12 p.Ala81Thr (c.241G>A) pathogenic?

ALG12 p.Ala81Thr (c.241G>A) is classified Uncertain significance in ALG12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-18). AlphaMissense: likely benign (0.0888); Ultra-rare (popmax 0.015%, amr); Associated with ALG12-congenital disorder of glycosylation.

What condition is associated with ALG12 p.Ala81Thr (c.241G>A)?

ALG12 p.Ala81Thr (c.241G>A) is associated with ALG12-congenital disorder of glycosylation (ClinVar).

How common is ALG12 p.Ala81Thr (c.241G>A) in the general population?

ALG12 p.Ala81Thr (c.241G>A) is ultra-rare (popmax 0.015%, amr) (gnomAD).

How is ALG12-CDG inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ALG12 p.Ala81Thr (c.241G>A)?

AlphaMissense predicts likely benign (score 0.0888) — an in-silico prediction, not a clinical call.

ALG12 p.Ala81Thr

c.241G>A · rs770434145 · VCV1381071

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0888 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ALG12-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.0888	likely benign
REVEL	0.511	indeterminate
SaProt	LLR -9.77	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.73	GERP -2.4
Regional constraint	o/e 0.95	unconstrained · MANE · 9,924 bp · p 0.17 · regional, not allelic
Overall
CADD	9.931	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.015% Admixed American · 9/60,012 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.00335% 54/1,613,882 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,668
Remaining individualsnot grpmax-eligible	0.0112%	8,926
African / African-American	0.004%	24,984
European (non-Finnish)	0.0028%	35,759
East Asian	0.00223%	44,896
South Asian	0.0011%	91,096

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.Ala81Thr
Coding: c.241G>A
MANE Select: NM_024105
dbSNP: rs770434145
Type: single nucleotide variant
Location: chr22:49913439 (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-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For ALG12-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG12 p.Ala81Val Conflicting classifications of pathogenicity ★ ⚠ same residue
ALG12 p.Ala81= 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.Arg146Gln Pathogenic/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

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-ala81thr (accessed [today's date]).

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