Is ALS2 p.Ala377Thr (c.1129G>A) pathogenic?

ALS2 p.Ala377Thr (c.1129G>A) is classified Uncertain significance in ALS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-30). AlphaMissense: likely benign (0.0617); Very rare (popmax 0.00687%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ALS2 p.Ala377Thr (c.1129G>A)?

ALS2 p.Ala377Thr (c.1129G>A) is associated with Inborn genetic diseases, infantile-onset ascending hereditary spastic paralysis (ClinVar).

How common is ALS2 p.Ala377Thr (c.1129G>A) in the general population?

ALS2 p.Ala377Thr (c.1129G>A) is very rare (popmax 0.00687%, nfe) (gnomAD).

What do computational predictors say about ALS2 p.Ala377Thr (c.1129G>A)?

AlphaMissense predicts likely benign (score 0.0617) — an in-silico prediction, not a clinical call.

ALS2 p.Ala377Thr

c.1129G>A · rs200990057 · VCV804517

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0617 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00687%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0617	likely benign
REVEL	0.013	strongly benign-leaning
SaProt	LLR -5.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.25	acceptor gain · deltas
Pangolin	Δ0.21	gain · loss 0.13 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.3	GERP -0.12, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0064 · regional, not allelic
Overall
CADD	19.94	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 0.00687% European (non-Finnish) · 81/1,179,878 alleles

Filtering AF 0.00563% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00546% 88/1,610,306 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00687%	14,566
Admixed American	0.005%	19,995
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00267%	37,515

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.Ala377Thr
Coding: c.1129G>A
MANE Select: NM_020919
dbSNP: rs200990057
Type: single nucleotide variant
Location: chr2:201757744 (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

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 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
ALS2 p.Arg1510Ter 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-ala377thr (accessed [today's date]).

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