Is ALG6 p.Phe336Leu (c.1008C>G) pathogenic?

ALG6 p.Phe336Leu (c.1008C>G) is classified Uncertain significance in ALG6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). AlphaMissense: likely pathogenic (0.9666); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with ALG6 p.Phe336Leu (c.1008C>G)?

ALG6 p.Phe336Leu (c.1008C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ALG6 p.Phe336Leu (c.1008C>G) in the general population?

ALG6 p.Phe336Leu (c.1008C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ALG6 p.Phe336Leu (c.1008C>G)?

AlphaMissense predicts likely pathogenic (score 0.9666) — an in-silico prediction, not a clinical call.

ALG6 p.Phe336Leu

c.1008C>G · VCV4038289

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9666 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9666	likely pathogenic · top 7% in ALG6
REVEL	0.858	moderately pathogenic-leaning
SaProt	LLR -11.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 66 kb · p 0.00074 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00167% Admixed American · 1/59,754 alleles

Overall 0.000137% 2/1,457,650 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,754
European (non-Finnish)	8.49e-05%	1,177,910

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.Phe336Leu
Coding: c.1008C>G
MANE Select: NM_013339
Type: single nucleotide variant
Location: chr1:63419390 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.08

Full ALG6 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

Similar variants

ALG6 p.Phe336fs Pathogenic/Likely pathogenic ★★ same residue
ALG6 p.Cys212Gly Uncertain significance ★★ ⚠ same condition
ALG6 p.Cys431Gly Uncertain significance ★★ ⚠ same condition
ALG6 p.Gly172Asp Uncertain significance ★★ ⚠ same condition
ALG6 p.Gly177Ser Uncertain significance ★★ ⚠ same condition
ALG6 p.Ile197Met Uncertain significance ★★ ⚠ same condition
ALG6 p.Met7Thr Uncertain significance ★★ ⚠ same condition
ALG6 p.Thr374Ala Uncertain significance ★★ ⚠ 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-phe336leu (accessed [today's date]).

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