Is ALS2 p.Cys178Phe (c.533G>T) pathogenic?

ALS2 p.Cys178Phe (c.533G>T) is classified Uncertain significance in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-04). AlphaMissense: ambiguous (0.3677); Rare (popmax 0.199%, mid); Associated with infantile-onset ascending hereditary spastic paralysis.

What condition is associated with ALS2 p.Cys178Phe (c.533G>T)?

ALS2 p.Cys178Phe (c.533G>T) is associated with infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Cys178Phe (c.533G>T) in the general population?

ALS2 p.Cys178Phe (c.533G>T) is rare (popmax 0.199%, mid) (gnomAD).

What do computational predictors say about ALS2 p.Cys178Phe (c.533G>T)?

AlphaMissense predicts ambiguous (score 0.3677) — an in-silico prediction, not a clinical call.

ALS2 p.Cys178Phe

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.533G>T · rs372000096 · VCV2136972

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3677 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.199%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

infantile-onset ascending hereditary spastic paralysis

Computational evidence

Protein change
AlphaMissense	0.3677	ambiguous
REVEL	0.837	moderately pathogenic-leaning
SaProt	LLR -7.18	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0064 · regional, not allelic
Overall
CADD	27.1	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 0.199% Middle Eastern · 12/6,044 alleles

Filtering AF 0.115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0898%

Overall 0.000871% 14/1,607,528 alleles · rare exomes 13/1,455,216 · genomes 1/152,312 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.199%	504
Remaining individualsnot grpmax-eligible	0.00161%	62,182
South Asian	0.0011%	90,778

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.Cys178Phe
Coding: c.533G>T
MANE Select: NM_020919
dbSNP: rs372000096
Type: single nucleotide variant
Location: chr2:201761461 (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

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ALS2 p.Ala573Glu Likely pathogenic ★★ same condition
ALS2 p.Arg1139Ter Pathogenic/Likely pathogenic ★★ same condition
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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-cys178phe (accessed [today's date]).

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