Is ALS2 p.Ser663Phe (c.1988C>T) pathogenic?

ALS2 p.Ser663Phe (c.1988C>T) is classified Uncertain significance in ALS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-05-30). AlphaMissense: likely benign (0.128); Very rare (popmax 0.00119%, nfe); Associated with infantile-onset ascending hereditary spastic paralysis.

What condition is associated with ALS2 p.Ser663Phe (c.1988C>T)?

ALS2 p.Ser663Phe (c.1988C>T) is associated with infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Ser663Phe (c.1988C>T) in the general population?

ALS2 p.Ser663Phe (c.1988C>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about ALS2 p.Ser663Phe (c.1988C>T)?

AlphaMissense predicts likely benign (score 0.128) — an in-silico prediction, not a clinical call.

ALS2 p.Ser663Phe

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.1988C>T · rs1410762746 · VCV1053618

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.128 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

infantile-onset ascending hereditary spastic paralysis

Computational evidence

Protein change
AlphaMissense	0.128	likely benign
REVEL	0.369	indeterminate
SaProt	LLR -9.43	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 0.89, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 56 kb · p 7.1e-07 · regional, not allelic
Overall
CADD	23.7	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 0.00119% European (non-Finnish) · 14/1,180,004 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000929% 15/1,614,010 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00119%	84,286
South Asian	0.0011%	91,084

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.Ser663Phe
Coding: c.1988C>T
MANE Select: NM_020919
dbSNP: rs1410762746
Type: single nucleotide variant
Location: chr2:201746576 (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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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-ser663phe (accessed [today's date]).

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