Is ALG6 p.Thr251Ala (c.751A>G) pathogenic?

ALG6 p.Thr251Ala (c.751A>G) is classified Benign/Likely benign in ALG6 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-30). AlphaMissense: likely benign (0.066); Low-frequency (popmax 2.26%, afr); Associated with ALG6-congenital disorder of glycosylation 1C.

What condition is associated with ALG6 p.Thr251Ala (c.751A>G)?

ALG6 p.Thr251Ala (c.751A>G) is associated with ALG6-congenital disorder of glycosylation 1C (ClinVar).

How common is ALG6 p.Thr251Ala (c.751A>G) in the general population?

ALG6 p.Thr251Ala (c.751A>G) is low-frequency (popmax 2.26%, afr) (gnomAD).

How is ALG6-CDG inherited?

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

What do computational predictors say about ALG6 p.Thr251Ala (c.751A>G)?

AlphaMissense predicts likely benign (score 0.066) — an in-silico prediction, not a clinical call.

ALG6 p.Thr251Ala

c.751A>G · rs61755863 · VCV128354

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.066 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.26%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG6-congenital disorder of glycosylation 1C

Computational evidence

Protein change
AlphaMissense	0.066	likely benign
REVEL	0.212	benign-leaning
SaProt	LLR -6.34	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 2.3	GERP 2.1, phastCons 0.3
Regional constraint	o/e 0.86	unconstrained · MANE · 66 kb · p 0.00074 · regional, not allelic
Overall
CADD	15.52	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 2.26% African / African-American · 1,697/75,000 alleles

Filtering AF 2.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.14%

Overall 0.124% 2,008/1,614,070 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.26%	44
Admixed American	0.177%	566
Remaining individualsnot grpmax-eligible	0.17%	590
Middle Eastern	0.033%	3,031
South Asian	0.00988%	10,120
European (non-Finnish)	0.00746%	13,409

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: ALG6
Protein: p.Thr251Ala
Coding: c.751A>G
MANE Select: NM_013339
dbSNP: rs61755863
Type: single nucleotide variant
Location: chr1:63411996 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.08

Full ALG6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG6-congenital disorder of glycosylation 1C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For ALG6-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG6 c.1128-1G>A Likely pathogenic ★★ same condition
ALG6 c.1128-2A>C Likely pathogenic ★★ same condition
ALG6 c.1326+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALG6 c.257+5G>A Pathogenic/Likely pathogenic ★★ same condition
ALG6 c.429+1G>T Likely pathogenic ★★ same condition
ALG6 c.495-2A>G Likely pathogenic ★★ same condition
ALG6 c.495-2A>T Likely pathogenic ★★ same condition
ALG6 c.680+1G>A 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/alg6-p-thr251ala (accessed [today's date]).

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