Is ALG6 p.Ser304Phe (c.911C>T) pathogenic?

ALG6 p.Ser304Phe (c.911C>T) is classified Benign/Likely benign in ALG6 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0439); Common (popmax 86.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with ALG6-congenital disorder of glycosylation 1C.

What condition is associated with ALG6 p.Ser304Phe (c.911C>T)?

ALG6 p.Ser304Phe (c.911C>T) is associated with ALG6-congenital disorder of glycosylation 1C (ClinVar).

How is ALG6-CDG inherited?

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

What do computational predictors say about ALG6 p.Ser304Phe (c.911C>T)?

AlphaMissense predicts likely benign (score 0.0439) — an in-silico prediction, not a clinical call.

ALG6 p.Ser304Phe

Q: How common is ALG6 p.Ser304Phe (c.911C>T) in the general population?

ALG6 p.Ser304Phe (c.911C>T) is common (popmax 86.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.911C>T · rs4630153 · VCV95531

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.0439 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 86.9%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG6-congenital disorder of glycosylation 1C

Computational evidence

Protein change
AlphaMissense	0.0439	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -5.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.25	acceptor loss, 8 bp away · masked 0 · deltas
Pangolin	Δ0.34	loss · gain 0.10 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.68	GERP -0.97, phastCons 0.011
Regional constraint	o/e 0.86	unconstrained · MANE · 66 kb · p 0.00074 · regional, not allelic
Overall
CADD	13.44	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 86.9% African / African-American · 64,905/74,720 alleles

Filtering AF 86.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 86.1%

Overall 71.8% 1,149,644/1,601,814 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	86.9%	1
South Asian	85.9%	1
East Asian	83.8%	1
Middle Eastern	82.4%	1
Admixed American	80.3%	1
Ashkenazi Jewishnot grpmax-eligible	78%	1
Remaining individualsnot grpmax-eligible	74.2%	1
Amishnot grpmax-eligible	69.8%	1
European (non-Finnish)	68.7%	1
Finnishnot grpmax-eligible	67.7%	1

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: ALG6
Protein: p.Ser304Phe
Coding: c.911C>T
MANE Select: NM_013339
dbSNP: rs4630153
Type: single nucleotide variant
Location: chr1:63415881 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.08
Residue 304: a UniProt-annotated variant site (decreased function in dolichol-linked oligosaccharide biosynthetic process as shown by rescue experiments of defective glycosylation in an alg6-deficient s.cerevisiae strain)

Full ALG6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG6-congenital disorder of glycosylation 1C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For ALG6-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG6 c.1128-1G>A Likely pathogenic ★★ same condition
ALG6 c.1128-2A>C Likely pathogenic ★★ same condition
ALG6 c.1326+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALG6 c.257+5G>A Pathogenic/Likely pathogenic ★★ same condition
ALG6 c.429+1G>T Likely pathogenic ★★ same condition
ALG6 c.495-2A>G Likely pathogenic ★★ same condition
ALG6 c.495-2A>T Likely pathogenic ★★ same condition
ALG6 c.680+1G>A Pathogenic/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/alg6-p-ser304phe (accessed [today's date]).

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