Is ALG1 p.Phe185Cys (c.554T>G) pathogenic?

ALG1 p.Phe185Cys (c.554T>G) is classified Benign/Likely benign in ALG1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1214); Low-frequency (popmax 4.46%, afr); Associated with ALG1-congenital disorder of glycosylation.

What condition is associated with ALG1 p.Phe185Cys (c.554T>G)?

ALG1 p.Phe185Cys (c.554T>G) is associated with ALG1-congenital disorder of glycosylation (ClinVar).

How common is ALG1 p.Phe185Cys (c.554T>G) in the general population?

ALG1 p.Phe185Cys (c.554T>G) is low-frequency (popmax 4.46%, 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.Phe185Cys (c.554T>G)?

AlphaMissense predicts likely benign (score 0.1214) — an in-silico prediction, not a clinical call.

ALG1 p.Phe185Cys

c.554T>G · rs112668461 · VCV384255

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1214 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.46%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG1-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.1214	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -11.15	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.71	GERP -3.3, phastCons 0.33
Regional constraint	o/e 1.27	unconstrained · MANE · 13 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	17.78	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 4.46% African / African-American · 3,346/75,028 alleles

Filtering AF 4.33% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.28%

Overall 0.25% 4,035/1,614,118 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.46%	22
Middle Eastern	0.412%	242
Remaining individualsnot grpmax-eligible	0.389%	257
Admixed American	0.327%	306
European (non-Finnish)	0.0186%	5,388
South Asian	0.00549%	18,216
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604

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.Phe185Cys
Coding: c.554T>G
MANE Select: NM_019109
dbSNP: rs112668461
Type: single nucleotide variant
Location: chr16:5077459 (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

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

Similar variants

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
ALG1 c.961+1G>A 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-phe185cys (accessed [today's date]).

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