Is ALG9 p.Arg554Trp (c.1660C>T) pathogenic?

ALG9 p.Arg554Trp (c.1660C>T) is classified Conflicting classifications of pathogenicity in ALG9 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-03-28). AlphaMissense: likely benign (0.1199); Very rare (popmax 0.00644%, nfe); Associated with ALG9-congenital disorder of glycosylation.

What condition is associated with ALG9 p.Arg554Trp (c.1660C>T)?

ALG9 p.Arg554Trp (c.1660C>T) is associated with ALG9-congenital disorder of glycosylation (ClinVar).

How common is ALG9 p.Arg554Trp (c.1660C>T) in the general population?

ALG9 p.Arg554Trp (c.1660C>T) is very rare (popmax 0.00644%, nfe) (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.Arg554Trp (c.1660C>T)?

AlphaMissense predicts likely benign (score 0.1199) — an in-silico prediction, not a clinical call.

ALG9 p.Arg554Trp

c.1660C>T · rs782084496 · VCV302425

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1199 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00644%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

ALG9-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.1199	likely benign
REVEL	0.471	indeterminate
SaProt	LLR -10.50	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 54 kb · p 0.028 · regional, not allelic
Overall
CADD	25.3	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 R547W vs ClinVar R554W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00644% European (non-Finnish) · 76/1,179,966 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00551% 89/1,613,894 alleles · very rare exomes 84/1,461,812 · genomes 5/152,082 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00937%	10,670
European (non-Finnish)grpmax	0.00644%	15,526
African / African-American	0.00401%	24,961
East Asian	0.00223%	44,896
Admixed American	0.00167%	59,980
Remaining individualsnot grpmax-eligible	0.0016%	62,480
South Asian	0.0011%	91,070

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: ALG9
Protein: p.Arg554Trp
Coding: c.1660C>T
MANE Select: NM_024740
dbSNP: rs782084496
Type: single nucleotide variant
Location: chr11:111809716 (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

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

For ALG9-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

ALG9 p.Arg554Gln Uncertain significance ★ ⚠ 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-arg554trp (accessed [today's date]).

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