Is ALS2 p.Arg1653His (c.4958G>A) pathogenic?

ALS2 p.Arg1653His (c.4958G>A) is classified Uncertain significance in ALS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-01). AlphaMissense: likely benign (0.0841); Ultra-rare (popmax 0.0379%, eas); Associated with Inborn genetic diseases.

What condition is associated with ALS2 p.Arg1653His (c.4958G>A)?

ALS2 p.Arg1653His (c.4958G>A) is associated with Inborn genetic diseases, amyotrophic lateral sclerosis type 2, juvenile, infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Arg1653His (c.4958G>A) in the general population?

ALS2 p.Arg1653His (c.4958G>A) is ultra-rare (popmax 0.0379%, eas) (gnomAD).

What do computational predictors say about ALS2 p.Arg1653His (c.4958G>A)?

AlphaMissense predicts likely benign (score 0.0841) — an in-silico prediction, not a clinical call.

ALS2 p.Arg1653His

c.4958G>A · rs190606035 · VCV333583

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0841 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0841	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -4.96	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 6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 56 kb · p 7.1e-07 · regional, not allelic
Overall
CADD	21.4	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 0.0379% East Asian · 17/44,802 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.00397% 64/1,613,730 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0379%	2,635
South Asian	0.0209%	4,792
Admixed American	0.00833%	11,998
Remaining individualsnot grpmax-eligible	0.0048%	20,828
African / African-American	0.004%	24,994
Finnishnot grpmax-eligible	0.00313%	31,999
European (non-Finnish)	0.00127%	78,657

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.Arg1653His
Coding: c.4958G>A
MANE Select: NM_020919
dbSNP: rs190606035
Type: single nucleotide variant
Location: chr2:201701867 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69
Residue 1653: the vps9 domain

Full ALS2 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: amyotrophic lateral sclerosis type 2, juvenile infantile-onset ascending hereditary spastic paralysis

Similar variants

ALS2 p.Arg1653Cys Uncertain significance ★★ ⚠ same residue
ALS2 c.1640+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALS2 c.2580+2T>C Pathogenic ★★ same condition
ALS2 c.3703-2A>G Pathogenic/Likely pathogenic ★★ same condition
ALS2 c.4626+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Ala573Glu Likely pathogenic ★★ same condition
ALS2 p.Arg1139Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Arg1421Ter Pathogenic/Likely pathogenic ★★ 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/als2-p-arg1653his (accessed [today's date]).

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