Is ALG9 p.Pro513Leu (c.1538C>T) pathogenic?

ALG9 p.Pro513Leu (c.1538C>T) is classified Benign/Likely benign in ALG9 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.0854); Rare (popmax 0.672%, sas); Associated with Gillessen-Kaesbach-Nishimura syndrome.

What condition is associated with ALG9 p.Pro513Leu (c.1538C>T)?

ALG9 p.Pro513Leu (c.1538C>T) is associated with Gillessen-Kaesbach-Nishimura syndrome, ALG9-congenital disorder of glycosylation (ClinVar).

How common is ALG9 p.Pro513Leu (c.1538C>T) in the general population?

ALG9 p.Pro513Leu (c.1538C>T) is rare (popmax 0.672%, sas) (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.Pro513Leu (c.1538C>T)?

AlphaMissense predicts likely benign (score 0.0854) — an in-silico prediction, not a clinical call.

ALG9 p.Pro513Leu

c.1538C>T · rs185149177 · VCV166678

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0854 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.672%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Gillessen-Kaesbach-Nishimura syndrome

Computational evidence

Protein change
AlphaMissense	0.0854	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -6.42	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 10	GERP 1.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 54 kb · p 0.028 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P506L vs ClinVar P513L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.672% South Asian · 612/91,072 alleles

Filtering AF 0.628% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.61%

Overall 0.337% 5,437/1,614,054 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.672%	149
Middle Eastern	0.528%	189
Amishnot grpmax-eligible	0.439%	228
European (non-Finnish)	0.371%	270
Remaining individualsnot grpmax-eligible	0.325%	308
Ashkenazi Jewishnot grpmax-eligible	0.287%	348
Admixed American	0.0966%	1,035
Finnishnot grpmax-eligible	0.0531%	1,883
African / African-American	0.048%	2,084

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.Pro513Leu
Coding: c.1538C>T
MANE Select: NM_024740
dbSNP: rs185149177
Type: single nucleotide variant
Location: chr11:111836229 (GRCh38)
Gene constraint: LOEUF 0.853 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.35 · 2 PDB

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

Disease context

Gillessen-Kaesbach-Nishimura syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ALG9-congenital disorder of glycosylation

For ALG9-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

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
ALG9 c.*1722C>T 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-pro513leu (accessed [today's date]).

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