Is ALG1 p.Leu6Phe (c.18G>T) pathogenic?

ALG1 p.Leu6Phe (c.18G>T) is classified Conflicting classifications of pathogenicity in ALG1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-21). AlphaMissense: likely benign (0.0742); Ultra-rare (popmax 0.0425%, eas); Associated with Inborn genetic diseases.

What condition is associated with ALG1 p.Leu6Phe (c.18G>T)?

ALG1 p.Leu6Phe (c.18G>T) is associated with Inborn genetic diseases, ALG1-congenital disorder of glycosylation (ClinVar).

How common is ALG1 p.Leu6Phe (c.18G>T) in the general population?

ALG1 p.Leu6Phe (c.18G>T) is ultra-rare (popmax 0.0425%, eas) (gnomAD).

What do computational predictors say about ALG1 p.Leu6Phe (c.18G>T)?

AlphaMissense predicts likely benign (score 0.0742) — an in-silico prediction, not a clinical call.

ALG1 p.Leu6Phe

c.18G>T · rs758274229 · VCV1574853

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0742 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0425%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0742	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -7.59	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 1.4	GERP -2.2, phastCons 0.004
Regional constraint	o/e 1.27	unconstrained · MANE · 13 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	9.44	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 0.0425% East Asian · 19/44,674 alleles

Filtering AF 0.0278% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0231%

Overall 0.00237% 38/1,604,960 alleles · ultra-rare exomes 31/1,452,598 · genomes 7/152,362 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0425%	2,351
South Asian	0.0133%	7,542
Remaining individualsnot grpmax-eligible	0.00643%	15,545
African / African-American	0.00133%	74,956
European (non-Finnish)	0.00017%	589,240

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.Leu6Phe
Coding: c.18G>T
MANE Select: NM_019109
dbSNP: rs758274229
Type: single nucleotide variant
Location: chr16:5071867 (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

Also linked: ALG1-congenital disorder of glycosylation

Similar variants

ALG1 p.Leu6= Likely benign ★ 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
ALG1 c.863-2A>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-leu6phe (accessed [today's date]).

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