Is ALG9 p.Arg247Ser (c.741G>T) pathogenic?

ALG9 p.Arg247Ser (c.741G>T) is classified Conflicting classifications of pathogenicity in ALG9 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-02-16). AlphaMissense: likely benign (0.2808); Ultra-rare (popmax 0.0368%, nfe); Associated with ALG9-related disorder.

What condition is associated with ALG9 p.Arg247Ser (c.741G>T)?

ALG9 p.Arg247Ser (c.741G>T) is associated with ALG9-related disorder, Gillessen-Kaesbach-Nishimura syndrome, ALG9-congenital disorder of glycosylation (ClinVar).

How common is ALG9 p.Arg247Ser (c.741G>T) in the general population?

ALG9 p.Arg247Ser (c.741G>T) is ultra-rare (popmax 0.0368%, nfe) (gnomAD).

What do computational predictors say about ALG9 p.Arg247Ser (c.741G>T)?

AlphaMissense predicts likely benign (score 0.2808) — an in-silico prediction, not a clinical call.

ALG9 p.Arg247Ser

c.741G>T · rs200946042 · VCV598383

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2808 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0368%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG9-related disorder

Computational evidence

Protein change
AlphaMissense	0.2808	likely benign
REVEL	0.176	moderately benign-leaning
SaProt	LLR -7.67	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 -1.1	GERP 0.19
Regional constraint	o/e 0.88	unconstrained · MANE · 27 kb · p 0.019 · regional, not allelic
Overall
CADD	15.74	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 0.0368% European (non-Finnish) · 434/1,180,014 alleles

Filtering AF 0.0339% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0327%

Overall 0.0291% 470/1,614,022 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0368%	2,719
Remaining individualsnot grpmax-eligible	0.0192%	5,207
East Asian	0.0134%	7,482
South Asian	0.00988%	10,121
Finnishnot grpmax-eligible	0.00625%	16,004
African / African-American	0.00534%	18,732
Admixed American	0.00167%	59,998

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.Arg247Ser
Coding: c.741G>T
MANE Select: NM_024740
dbSNP: rs200946042
Type: single nucleotide variant
Location: chr11:111853697 (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-related disorder

Also linked: Gillessen-Kaesbach-Nishimura syndrome ALG9-congenital disorder of glycosylation

Similar variants

ALG9 p.Arg247Gly 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-arg247ser (accessed [today's date]).

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