Is ALG1 p.Ser258Leu (c.773C>T) pathogenic?

ALG1 p.Ser258Leu (c.773C>T) is classified Pathogenic/Likely pathogenic in ALG1 (ClinVar, Multiple submitters, 21 submitters; last evaluated 2026-05-29). AlphaMissense: ambiguous (0.4312); Ultra-rare (popmax 0.0786%, nfe); Associated with ALG1-related disorder.

What condition is associated with ALG1 p.Ser258Leu (c.773C>T)?

ALG1 p.Ser258Leu (c.773C>T) is associated with ALG1-related disorder, congenital nephrotic syndrome, Finnish type, ALG12-congenital disorder of glycosylation (ClinVar).

How common is ALG1 p.Ser258Leu (c.773C>T) in the general population?

ALG1 p.Ser258Leu (c.773C>T) is ultra-rare (popmax 0.0786%, nfe) (gnomAD).

What do computational predictors say about ALG1 p.Ser258Leu (c.773C>T)?

AlphaMissense predicts ambiguous (score 0.4312) — an in-silico prediction, not a clinical call.

ALG1 p.Ser258Leu

c.773C>T · rs28939378 · VCV4724

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 21 submitters

AlphaMissense

ambiguous

0.4312 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0786%, nfe)

Conditions

ALG1-related disorder

Computational evidence

Protein change
AlphaMissense	0.4312	ambiguous
REVEL	0.615	indeterminate
SaProt	LLR -13.37	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 13 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	23.7	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 0.0786% European (non-Finnish) · 927/1,179,794 alleles

Filtering AF 0.0743% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0726%

Overall 0.0604% 974/1,612,744 alleles · ultra-rare exomes 924/1,460,556 · genomes 50/152,188 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0786%	1,273
Remaining individualsnot grpmax-eligible	0.0385%	2,599
Finnishnot grpmax-eligible	0.0125%	8,001
African / African-American	0.012%	8,322
Admixed American	0.00833%	12,000
South Asian	0.0011%	91,018

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.Ser258Leu
Coding: c.773C>T
MANE Select: NM_019109
dbSNP: rs28939378
Type: single nucleotide variant
Location: chr16:5078789 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.24
Residue 258: a UniProt-annotated variant site (in cdg1k; decreased function in protein glycosylation as shown by rescue assays in an alg1-deficient yeast strain); the 'disordered' region

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

Disease context

ALG1-related disorder

Also linked: congenital nephrotic syndrome, Finnish type ALG12-congenital disorder of glycosylation ALG1-congenital disorder of glycosylation congenital disorder of glycosylation

Similar variants

ALG1 p.Ser258= Likely benign ★ same residue
ALG1 p.Ser258_Arg263dup Uncertain significance ★ same residue
ALG1 c.1187+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALG1 c.1187+2T>C Pathogenic ★★ same condition
ALG1 c.1188-2A>G Pathogenic/Likely pathogenic ★★ same condition
ALG1 c.209-2A>G Likely pathogenic ★★ same condition
ALG1 c.539+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALG1 c.630-2A>G 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/alg1-p-ser258leu (accessed [today's date]).

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