Is ALS2 p.Pro372Arg (c.1115C>G) pathogenic?

ALS2 p.Pro372Arg (c.1115C>G) is classified Conflicting classifications of pathogenicity in ALS2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0813); Rare (popmax 0.578%, mid); Associated with ALS2-related disorder.

What condition is associated with ALS2 p.Pro372Arg (c.1115C>G)?

ALS2 p.Pro372Arg (c.1115C>G) is associated with ALS2-related disorder, amyotrophic lateral sclerosis type 2, juvenile, juvenile primary lateral sclerosis (ClinVar).

How common is ALS2 p.Pro372Arg (c.1115C>G) in the general population?

ALS2 p.Pro372Arg (c.1115C>G) is rare (popmax 0.578%, mid) (gnomAD).

What do computational predictors say about ALS2 p.Pro372Arg (c.1115C>G)?

AlphaMissense predicts likely benign (score 0.0813) — an in-silico prediction, not a clinical call.

ALS2 p.Pro372Arg

c.1115C>G · rs190369242 · VCV241307

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0813 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.578%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALS2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0813	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -7.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.88, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0064 · regional, not allelic
Overall
CADD	21.4	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 0.578% Middle Eastern · 35/6,058 alleles

Filtering AF 0.427% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.375%

Overall 0.142% 2,272/1,603,366 alleles · rare exomes 2,124/1,451,118 · genomes 148/152,248 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.578%	173
South Asian	0.236%	423
Remaining individualsnot grpmax-eligible	0.188%	533
European (non-Finnish)	0.154%	648
Admixed American	0.0917%	1,090
African / African-American	0.032%	3,122
Ashkenazi Jewishnot grpmax-eligible	0.0237%	4,223
Finnishnot grpmax-eligible	0.00864%	11,577

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.Pro372Arg
Coding: c.1115C>G
MANE Select: NM_020919
dbSNP: rs190369242
Type: single nucleotide variant
Location: chr2:201757758 (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 juvenile primary lateral sclerosis infantile-onset ascending hereditary spastic paralysis hereditary spastic paraplegia

Similar variants

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
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-pro372arg (accessed [today's date]).

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