Is ALG8 p.Thr35Ile (c.104C>T) pathogenic?

ALG8 p.Thr35Ile (c.104C>T) is classified Uncertain significance in ALG8 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-05-08). AlphaMissense: likely pathogenic (0.8497); Ultra-rare (popmax 0.0165%, mid).

How common is ALG8 p.Thr35Ile (c.104C>T) in the general population?

ALG8 p.Thr35Ile (c.104C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ALG8 p.Thr35Ile (c.104C>T)?

AlphaMissense predicts likely pathogenic (score 0.8497) — an in-silico prediction, not a clinical call.

ALG8 p.Thr35Ile

c.104C>T · rs866672190 · VCV3043654

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8497 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8497	likely pathogenic
REVEL	0.898	moderately pathogenic-leaning
SaProt	LLR -12.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.31	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 39 kb · p 0.14 · regional, not allelic
Overall
CADD	28.7	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 0.0165% Middle Eastern · 1/6,062 alleles

Overall 6.84e-05% 1/1,461,398 alleles · ultra-rare

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: ALG8
Protein: p.Thr35Ile
Coding: c.104C>T
MANE Select: NM_024079
dbSNP: rs866672190
Type: single nucleotide variant
Location: chr11:78127428 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07

Full ALG8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALG8 p.Thr35Ala Uncertain significance ★ ⚠ same residue
ALG8 c.368+2T>G Likely pathogenic ★★ same type
ALG8 c.674-2A>G Likely pathogenic ★★ same type
ALG8 c.777+1G>A Likely pathogenic ★★ same type
ALG8 c.95+1G>A Likely pathogenic ★★ same type
ALG8 p.Arg179Ter Pathogenic/Likely pathogenic ★★ same type
ALG8 p.Arg229Ter Pathogenic/Likely pathogenic ★★ same type
ALG8 p.Arg268Ter Pathogenic/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/alg8-p-thr35ile (accessed [today's date]).

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