Is ALG1 p.Ser444Leu (c.1331C>T) pathogenic?

ALG1 p.Ser444Leu (c.1331C>T) is classified Uncertain significance in ALG1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-07). AlphaMissense: likely benign (0.1151); Very rare (popmax 0.00333%, amr); Associated with ALG1-congenital disorder of glycosylation.

What condition is associated with ALG1 p.Ser444Leu (c.1331C>T)?

ALG1 p.Ser444Leu (c.1331C>T) is associated with ALG1-congenital disorder of glycosylation (ClinVar).

How common is ALG1 p.Ser444Leu (c.1331C>T) in the general population?

ALG1 p.Ser444Leu (c.1331C>T) is very rare (popmax 0.00333%, amr) (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.Ser444Leu (c.1331C>T)?

AlphaMissense predicts likely benign (score 0.1151) — an in-silico prediction, not a clinical call.

ALG1 p.Ser444Leu

c.1331C>T · rs397839861 · VCV1440202

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1151 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ALG1-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.1151	likely benign
REVEL	0.334	indeterminate
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 13 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	20.4	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 0.00333% Admixed American · 2/59,988 alleles

Filtering AF 0.000954% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00338% 54/1,596,326 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0637%	1,569
Admixed Americangrpmax	0.00333%	29,994
African / African-American	0.00267%	37,428
European (non-Finnish)	0.00153%	65,543
South Asian	0.0011%	90,996

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser444Leu
Coding: c.1331C>T
MANE Select: NM_201400 · reported on NM_019109
dbSNP: rs397839861
Type: single nucleotide variant
Location: chr16:5084817 (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-ser444leu (accessed [today's date]).

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