Is ALG3 p.Pro39Leu (c.116C>T) pathogenic?

ALG3 p.Pro39Leu (c.116C>T) is classified Uncertain significance in ALG3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-17). AlphaMissense: likely pathogenic (0.6653); Very rare (popmax 0.00501%, amr).

How common is ALG3 p.Pro39Leu (c.116C>T) in the general population?

ALG3 p.Pro39Leu (c.116C>T) is very rare (popmax 0.00501%, amr) (gnomAD).

What do computational predictors say about ALG3 p.Pro39Leu (c.116C>T)?

AlphaMissense predicts likely pathogenic (score 0.6653) — an in-silico prediction, not a clinical call.

ALG3 p.Pro39Leu

c.116C>T · rs1348594417 · VCV3251910

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6653 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6653	likely pathogenic
REVEL	0.668	pathogenic-leaning
SaProt	LLR -16.66	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 12	GERP 1.5, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 3,742 bp · p 0.14 · regional, not allelic
Overall
CADD	27.9	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 0.00501% Admixed American · 3/59,832 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000669%

Overall 0.000206% 3/1,456,426 alleles · very 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: ALG3
Protein: p.Pro39Leu
Coding: c.116C>T
MANE Select: NM_005787
dbSNP: rs1348594417
Type: single nucleotide variant
Location: chr3:184248825 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.05

Full ALG3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALG3 p.Pro39fs Pathogenic ★ same residue
ALG3 c.444+1G>T Likely pathogenic ★★ same type
ALG3 p.Arg171Gln Pathogenic/Likely pathogenic ★★ same type
ALG3 p.Arg266Cys Pathogenic ★★ same type
ALG3 p.Arg354Cys Likely pathogenic ★★ same type
ALG3 p.Arg354His Pathogenic/Likely pathogenic ★★ same type
ALG3 p.Asn174Ser Likely pathogenic ★★ ⚠ same type
ALG3 p.Gly55= 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/alg3-p-pro39leu (accessed [today's date]).

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