Is ALS2 p.Ser1335= (c.4005T>C) pathogenic?

ALS2 p.Ser1335= (c.4005T>C) is classified Conflicting classifications of pathogenicity in ALS2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-07). Ultra-rare (popmax 0.0477%, sas); Associated with Inborn genetic diseases.

What condition is associated with ALS2 p.Ser1335= (c.4005T>C)?

ALS2 p.Ser1335= (c.4005T>C) is associated with Inborn genetic diseases, infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Ser1335= (c.4005T>C) in the general population?

ALS2 p.Ser1335= (c.4005T>C) is ultra-rare (popmax 0.0477%, sas) (gnomAD).

ALS2 p.Ser1335=

c.4005T>C · rs541714751 · VCV2627981

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0477%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.2	GERP -1.4, phastCons 1
Overall
CADD	12.16	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0477% South Asian · 43/90,060 alleles

Filtering AF 0.0364% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0324%

Overall 0.00307% 48/1,561,992 alleles · ultra-rare exomes 46/1,409,686 · genomes 2/152,306 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0477%	2,094
Remaining individualsnot grpmax-eligible	0.00494%	20,237
African / African-American	0.00135%	74,018
European (non-Finnish)	8.82e-05%	1,133,308

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.Ser1335=
Coding: c.4005T>C
MANE Select: NM_020919
dbSNP: rs541714751
Type: single nucleotide variant
Location: chr2:201711108 (GRCh38)
Gene constraint: LOEUF 0.649 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.69
Residue 1335: a modified residue (phosphoserine)

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: infantile-onset ascending hereditary spastic paralysis

Similar variants

ALS2 p.Ser1335Arg 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-ser1335 (accessed [today's date]).

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