Is ALG1 p.Val454Met (c.1360G>A) pathogenic?

ALG1 p.Val454Met (c.1360G>A) is classified Uncertain significance in ALG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-03). AlphaMissense: likely benign (0.0704); Very rare (popmax 0.00401%, afr); Associated with ALG1-congenital disorder of glycosylation.

What condition is associated with ALG1 p.Val454Met (c.1360G>A)?

ALG1 p.Val454Met (c.1360G>A) is associated with ALG1-congenital disorder of glycosylation (ClinVar).

How common is ALG1 p.Val454Met (c.1360G>A) in the general population?

ALG1 p.Val454Met (c.1360G>A) is very rare (popmax 0.00401%, afr) (gnomAD).

How is ALG1-CDG inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ALG1 p.Val454Met (c.1360G>A)?

AlphaMissense predicts likely benign (score 0.0704) — an in-silico prediction, not a clinical call.

ALG1 p.Val454Met

c.1360G>A · rs1957095896 · VCV1436988

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0704 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG1-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.0704	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -7.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.36	GERP -3.6, phastCons 0.005
Regional constraint	o/e 1.27	unconstrained · MANE · 13 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	12.69	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 0.00401% African / African-American · 3/74,864 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000188% 3/1,596,376 alleles · very rare

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.Val454Met
Coding: c.1360G>A
MANE Select: NM_201400 · reported on NM_019109
dbSNP: rs1957095896
Type: single nucleotide variant
Location: chr16:5084846 (GRCh38)

Full ALG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG1-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For ALG1-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

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-val454met (accessed [today's date]).

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