Is ALG2 p.Glu235Lys (c.703G>A) pathogenic?

ALG2 p.Glu235Lys (c.703G>A) is classified Uncertain significance in ALG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-09). AlphaMissense: likely pathogenic (0.933); Very rare (popmax 0.00266%, afr); Associated with Inborn genetic diseases.

What condition is associated with ALG2 p.Glu235Lys (c.703G>A)?

ALG2 p.Glu235Lys (c.703G>A) is associated with Inborn genetic diseases, ALG2-congenital disorder of glycosylation, congenital myasthenic syndrome 14 (ClinVar).

How common is ALG2 p.Glu235Lys (c.703G>A) in the general population?

ALG2 p.Glu235Lys (c.703G>A) is very rare (popmax 0.00266%, afr) (gnomAD).

What do computational predictors say about ALG2 p.Glu235Lys (c.703G>A)?

AlphaMissense predicts likely pathogenic (score 0.933) — an in-silico prediction, not a clinical call.

ALG2 p.Glu235Lys

c.703G>A · rs189167741 · VCV1004082

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.933 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.933	likely pathogenic
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -16.53	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 3,957 bp · p 0.038 · regional, not allelic
Overall
CADD	29.3	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00266% African / African-American · 2/75,056 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00167% 27/1,614,228 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00312%	32,015
African / African-Americangrpmax	0.00266%	37,528
European (non-Finnish)	0.00186%	53,639
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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: ALG2
Protein: p.Glu235Lys
Coding: c.703G>A
MANE Select: NM_033087
dbSNP: rs189167741
Type: single nucleotide variant
Location: chr9:99218482 (GRCh38)
Gene constraint: LOEUF 1.408 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.03

Full ALG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ALG2-congenital disorder of glycosylation congenital myasthenic syndrome 14

Similar variants

ALG2 p.Ala29Pro Uncertain significance ★★ ⚠ same condition
ALG2 p.Ala36Val Uncertain significance ★★ ⚠ same condition
ALG2 p.Ala71Gly Uncertain significance ★★ ⚠ same condition
ALG2 p.Ala71Val Uncertain significance ★★ ⚠ same condition
ALG2 p.Arg129Gln Uncertain significance ★★ ⚠ same condition
ALG2 p.Arg130Gln Uncertain significance ★★ ⚠ same condition
ALG2 p.Arg251His Uncertain significance ★★ ⚠ same condition
ALG2 p.Arg378Cys 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/alg2-p-glu235lys (accessed [today's date]).

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