Is ALS2 p.Ser654Arg (c.1960A>C) pathogenic?

ALS2 p.Ser654Arg (c.1960A>C) is classified Uncertain significance in ALS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-18). AlphaMissense: likely benign (0.1008); Very rare (popmax 0.00229%, nfe); Associated with infantile-onset ascending hereditary spastic paralysis.

What condition is associated with ALS2 p.Ser654Arg (c.1960A>C)?

ALS2 p.Ser654Arg (c.1960A>C) is associated with infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Ser654Arg (c.1960A>C) in the general population?

ALS2 p.Ser654Arg (c.1960A>C) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about ALS2 p.Ser654Arg (c.1960A>C)?

AlphaMissense predicts likely benign (score 0.1008) — an in-silico prediction, not a clinical call.

ALS2 p.Ser654Arg

Q: How is Infantile-onset ascending hereditary spastic paralysis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1960A>C · rs61757690 · VCV804519

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1008 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

infantile-onset ascending hereditary spastic paralysis

Computational evidence

Protein change
AlphaMissense	0.1008	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -7.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	donor gain · deltas
Constraint at this position
Conservation	phyloP 1.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 56 kb · p 7.1e-07 · regional, not allelic
Overall
CADD	20.6	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 0.00229% European (non-Finnish) · 27/1,180,026 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00173% 28/1,614,196 alleles · very rare exomes 28/1,461,882 · genomes 0/152,314 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00229%	43,705
Remaining individualsnot grpmax-eligible	0.0016%	62,512

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.Ser654Arg
Coding: c.1960A>C
MANE Select: NM_020919
dbSNP: rs61757690
Type: single nucleotide variant
Location: chr2:201746604 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69

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

Disease context

infantile-onset ascending hereditary spastic paralysis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Infantile-onset ascending hereditary spastic paralysis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALS2 p.Ser654Gly 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 p.Ala573Glu Likely pathogenic ★★ same condition
ALS2 p.Arg1139Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Arg1421Ter Pathogenic/Likely pathogenic ★★ same condition
ALS2 p.Arg1461Ter 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-ser654arg (accessed [today's date]).

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