Is ALG12 p.Thr323Met (c.968C>T) pathogenic?

ALG12 p.Thr323Met (c.968C>T) is classified Uncertain significance in ALG12 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-02). AlphaMissense: likely benign (0.0949); Very rare (popmax 0.00445%, eas); Associated with Inborn genetic diseases.

What condition is associated with ALG12 p.Thr323Met (c.968C>T)?

ALG12 p.Thr323Met (c.968C>T) is associated with Inborn genetic diseases, ALG12-congenital disorder of glycosylation (ClinVar).

How common is ALG12 p.Thr323Met (c.968C>T) in the general population?

ALG12 p.Thr323Met (c.968C>T) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about ALG12 p.Thr323Met (c.968C>T)?

AlphaMissense predicts likely benign (score 0.0949) — an in-silico prediction, not a clinical call.

ALG12 p.Thr323Met

c.968C>T · rs754936149 · VCV1419361

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0949 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0949	likely benign
REVEL	0.158	moderately benign-leaning
SaProt	LLR -7.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -2.6, phastCons 0.002
Regional constraint	o/e 0.95	unconstrained · MANE · 9,924 bp · p 0.17 · regional, not allelic
Overall
CADD	12.58	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 0.00445% East Asian · 2/44,902 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.00124% 20/1,614,008 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00782%	12,786
East Asiangrpmax	0.00445%	22,451
South Asian	0.0011%	91,090
European (non-Finnish)	0.00102%	98,337

Finnish 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.Thr323Met
Coding: c.968C>T
MANE Select: NM_024105
dbSNP: rs754936149
Type: single nucleotide variant
Location: chr22:49907745 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ALG12-congenital disorder of glycosylation

Similar variants

ALG12 p.Thr323= 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
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-thr323met (accessed [today's date]).

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