Is ALG9 p.Ser255Leu (c.764C>T) pathogenic?

ALG9 p.Ser255Leu (c.764C>T) is classified Benign/Likely benign in ALG9 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.162); Low-frequency (popmax 4.15%, afr); Associated with ALG9-congenital disorder of glycosylation.

What condition is associated with ALG9 p.Ser255Leu (c.764C>T)?

ALG9 p.Ser255Leu (c.764C>T) is associated with ALG9-congenital disorder of glycosylation, Gillessen-Kaesbach-Nishimura syndrome (ClinVar).

How common is ALG9 p.Ser255Leu (c.764C>T) in the general population?

ALG9 p.Ser255Leu (c.764C>T) is low-frequency (popmax 4.15%, afr) (gnomAD).

How is ALG9-CDG inherited?

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

What do computational predictors say about ALG9 p.Ser255Leu (c.764C>T)?

AlphaMissense predicts likely benign (score 0.162) — an in-silico prediction, not a clinical call.

ALG9 p.Ser255Leu

c.764C>T · rs17113312 · VCV96136

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.162 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.15%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG9-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.162	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -13.65	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 27 kb · p 0.019 · regional, not allelic
Overall
CADD	23.5	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 4.15% African / African-American · 3,111/74,994 alleles

Filtering AF 4.03% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.98%

Overall 0.213% 3,437/1,613,976 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.15%	24
Remaining individualsnot grpmax-eligible	0.259%	386
Admixed American	0.208%	480
Middle Eastern	0.115%	866
South Asian	0.00549%	18,206
European (non-Finnish)	0.00229%	43,704

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: ALG9
Protein: p.Ser255Leu
Coding: c.764C>T
MANE Select: NM_024740
dbSNP: rs17113312
Type: single nucleotide variant
Location: chr11:111853674 (GRCh38)
Gene constraint: LOEUF 0.853 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.35 · 2 PDB
Residue 255: a UniProt-annotated variant site (in)

Full ALG9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG9-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Gillessen-Kaesbach-Nishimura syndrome

For ALG9-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

ALG9 p.Ser255= Likely benign ★★ same residue
ALG9 c.566-1G>A Pathogenic/Likely pathogenic ★★ same condition
ALG9 c.896-2A>G Likely pathogenic ★★ same condition
ALG9 p.Arg143Ter Pathogenic/Likely pathogenic ★★ same condition
ALG9 p.Trp248Ter Pathogenic/Likely pathogenic ★★ same condition
ALG9 p.Tyr287Cys Pathogenic/Likely pathogenic ★★ same condition
ALG9 c.*1607C>T Uncertain significance ★★ same condition
ALG9 c.*1624A>C 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/alg9-p-ser255leu (accessed [today's date]).

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