Is ALS2 p.His1103= (c.3309T>C) pathogenic?

ALS2 p.His1103= (c.3309T>C) is classified Benign/Likely benign in ALS2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-15). Rare (popmax 0.52%, afr); Associated with ALS2-related disorder.

How common is ALS2 p.His1103= (c.3309T>C) in the general population?

ALS2 p.His1103= (c.3309T>C) is rare (popmax 0.52%, afr) (gnomAD).

ALS2 p.His1103=

Q: What condition is associated with ALS2 p.His1103= (c.3309T>C)?

ALS2 p.His1103= (c.3309T>C) is associated with ALS2-related disorder, amyotrophic lateral sclerosis type 2, juvenile, infantile-onset ascending hereditary spastic paralysis (ClinVar).

c.3309T>C · rs201920363 · VCV465189

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.52%, afr)

Conditions

ALS2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.2	GERP -3.4, phastCons 0.005
Overall
CADD	2.748	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.52% African / African-American · 390/75,018 alleles

Filtering AF 0.477% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.461%

Overall 0.044% 710/1,614,044 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.52%	192
Remaining individualsnot grpmax-eligible	0.0608%	1,645
Admixed American	0.0367%	2,728
European (non-Finnish)	0.0217%	4,609
Middle Eastern	0.0165%	6,062
South Asian	0.00329%	30,363

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.His1103=
Coding: c.3309T>C
MANE Select: NM_020919
dbSNP: rs201920363
Type: single nucleotide variant
Location: chr2:201725394 (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

Also linked: amyotrophic lateral sclerosis type 2, juvenile infantile-onset ascending hereditary spastic paralysis

Similar variants

ALS2 p.His1103Asn Uncertain significance ★★ ⚠ same residue
ALS2 p.His1103Tyr 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

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-his1103 (accessed [today's date]).

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