Is ALG1 p.Ala431Glu (c.1292C>A) pathogenic?

ALG1 p.Ala431Glu (c.1292C>A) is classified Uncertain significance in ALG1 (ClinVar, Single submitter, 4 submitters; last evaluated 2023-03-24). AlphaMissense: likely benign (0.1064); Ultra-rare (popmax 0.0108%, afr); Associated with Inborn genetic diseases.

What condition is associated with ALG1 p.Ala431Glu (c.1292C>A)?

ALG1 p.Ala431Glu (c.1292C>A) is associated with Inborn genetic diseases (ClinVar).

How common is ALG1 p.Ala431Glu (c.1292C>A) in the general population?

ALG1 p.Ala431Glu (c.1292C>A) is ultra-rare (popmax 0.0108%, afr) (gnomAD).

What do computational predictors say about ALG1 p.Ala431Glu (c.1292C>A)?

AlphaMissense predicts likely benign (score 0.1064) — an in-silico prediction, not a clinical call.

ALG1 p.Ala431Glu

c.1292C>A · rs370439294 · VCV1048859

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1064 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0108%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1064	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -5.67	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 0.28	GERP -2.3, phastCons 0.001
Regional constraint	o/e 1.27	unconstrained · MANE · 13 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	3.161	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 0.0108% African / African-American · 8/74,350 alleles

Filtering AF 0.00531% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00383%

Overall 0.00727% 11/151,346 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0108%	9,294
South Asian	0.0011%	90,880
European (non-Finnish)	0.00017%	589,779

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: ALG1
Protein: p.Ala431Glu
Coding: c.1292C>A
MANE Select: NM_019109
dbSNP: rs370439294
Type: single nucleotide variant
Location: chr16:5084778 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.24

Full ALG1 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

Similar variants

ALG1 p.Ala431= Uncertain significance ★★ same residue
ALG1 p.Ala431Val Conflicting classifications of pathogenicity ★ ⚠ same residue
ALG1 p.Ala360Val Pathogenic/Likely pathogenic ★★ same condition
ALG1 p.Gln342Pro Pathogenic/Likely pathogenic ★★ ⚠ same condition
ALG1 p.Ala278Thr Uncertain significance ★★ ⚠ same condition
ALG1 p.Arg257Gln Uncertain significance ★★ ⚠ same condition
ALG1 p.Asn311Lys Uncertain significance ★★ ⚠ same condition
ALG1 p.Asn80His Uncertain significance ★★ ⚠ 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/alg1-p-ala431glu (accessed [today's date]).

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