Is ALG9 p.Arg435Cys (c.1303C>T) pathogenic?

ALG9 p.Arg435Cys (c.1303C>T) is classified Uncertain significance in ALG9 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-07-20). AlphaMissense: likely pathogenic (0.9221); Very rare (popmax 0.00223%, eas); Associated with ALG9-congenital disorder of glycosylation.

What condition is associated with ALG9 p.Arg435Cys (c.1303C>T)?

ALG9 p.Arg435Cys (c.1303C>T) is associated with ALG9-congenital disorder of glycosylation (ClinVar).

How common is ALG9 p.Arg435Cys (c.1303C>T) in the general population?

ALG9 p.Arg435Cys (c.1303C>T) is very rare (popmax 0.00223%, eas) (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.Arg435Cys (c.1303C>T)?

AlphaMissense predicts likely pathogenic (score 0.9221) — an in-silico prediction, not a clinical call.

ALG9 p.Arg435Cys

c.1303C>T · VCV4887024

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9221 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG9-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.9221	likely pathogenic
REVEL	0.749	pathogenic-leaning
SaProt	LLR -14.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.22	donor loss, 21 bp away · masked 0 · deltas
Pangolin	Δ0.23	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 54 kb · p 0.028 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R428C vs ClinVar R435C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,888 alleles

Overall 0.000248% 4/1,613,994 alleles · very rare exomes 3/1,461,830 · genomes 1/152,164 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,888
Finnishnot grpmax-eligible	0.00156%	64,028
African / African-American	0.00134%	74,900
European (non-Finnish)	8.47e-05%	1,180,011

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.Arg435Cys
Coding: c.1303C>T
MANE Select: NM_024740
Type: single nucleotide variant
Location: chr11:111838270 (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 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-arg435cys (accessed [today's date]).

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