Is ALG6 p.Phe35Ile (c.103T>A) pathogenic?

ALG6 p.Phe35Ile (c.103T>A) is classified Uncertain significance in ALG6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-21). AlphaMissense: likely pathogenic (0.9228); Very rare (popmax 6.2e-05%).

How common is ALG6 p.Phe35Ile (c.103T>A) in the general population?

ALG6 p.Phe35Ile (c.103T>A) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about ALG6 p.Phe35Ile (c.103T>A)?

AlphaMissense predicts likely pathogenic (score 0.9228) — an in-silico prediction, not a clinical call.

ALG6 p.Phe35Ile

c.103T>A · rs2100404930 · VCV1690669

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9228 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9228	likely pathogenic
REVEL	0.855	moderately pathogenic-leaning
SaProt	LLR -14.20	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 66 kb · p 0.00074 · regional, not allelic
Overall
CADD	26.8	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 6.2e-05%

Overall 6.2e-05% 1/1,614,122 alleles · very rare exomes 1/1,461,810 · genomes 0/152,312 · joint denominator

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.Phe35Ile
Coding: c.103T>A
MANE Select: NM_013339
dbSNP: rs2100404930
Type: single nucleotide variant
Location: chr1:63396533 (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

Similar variants

ALG6 p.Phe35Ser Uncertain significance ★ ⚠ same residue
ALG6 c.1128-1G>A Likely pathogenic ★★ same type
ALG6 c.1128-2A>C Likely pathogenic ★★ same type
ALG6 c.1326+1G>A Pathogenic/Likely pathogenic ★★ same type
ALG6 c.257+5G>A Pathogenic/Likely pathogenic ★★ same type
ALG6 c.429+1G>T Likely pathogenic ★★ same type
ALG6 c.495-2A>G Likely pathogenic ★★ same type
ALG6 c.495-2A>T Likely pathogenic ★★ same type

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-phe35ile (accessed [today's date]).

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