Is ALS2 p.Gln817Arg (c.2450A>G) pathogenic?

ALS2 p.Gln817Arg (c.2450A>G) is classified Uncertain significance in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely benign (0.09); Very rare (popmax 0.000848%, nfe); Associated with ALS2-related disorder.

What condition is associated with ALS2 p.Gln817Arg (c.2450A>G)?

ALS2 p.Gln817Arg (c.2450A>G) is associated with ALS2-related disorder, amyotrophic lateral sclerosis type 2, juvenile (ClinVar).

How common is ALS2 p.Gln817Arg (c.2450A>G) in the general population?

ALS2 p.Gln817Arg (c.2450A>G) is very rare (popmax 0.000848%, nfe) (gnomAD).

What do computational predictors say about ALS2 p.Gln817Arg (c.2450A>G)?

AlphaMissense predicts likely benign (score 0.09) — an in-silico prediction, not a clinical call.

ALS2 p.Gln817Arg

c.2450A>G · rs751084476 · VCV895143

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.09 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALS2-related disorder

Computational evidence

Protein change
AlphaMissense	0.09	likely benign
REVEL	0.178	moderately benign-leaning
SaProt	LLR -5.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 56 kb · p 7.1e-07 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000848% European (non-Finnish) · 10/1,179,874 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.00062% 10/1,613,648 alleles · very rare

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: ALS2
Protein: p.Gln817Arg
Coding: c.2450A>G
MANE Select: NM_020919
dbSNP: rs751084476
Type: single nucleotide variant
Location: chr2:201733406 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69
Residue 817: the dh domain

Full ALS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: amyotrophic lateral sclerosis type 2, juvenile

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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/als2-p-gln817arg (accessed [today's date]).

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