Is ALG3 p.Pro332His (c.995C>A) pathogenic?

ALG3 p.Pro332His (c.995C>A) is classified Uncertain significance in ALG3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.0858); Ultra-rare (popmax 0.0283%, amr); Associated with Inborn genetic diseases.

What condition is associated with ALG3 p.Pro332His (c.995C>A)?

ALG3 p.Pro332His (c.995C>A) is associated with Inborn genetic diseases (ClinVar).

How common is ALG3 p.Pro332His (c.995C>A) in the general population?

ALG3 p.Pro332His (c.995C>A) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

What do computational predictors say about ALG3 p.Pro332His (c.995C>A)?

AlphaMissense predicts likely benign (score 0.0858) — an in-silico prediction, not a clinical call.

ALG3 p.Pro332His

c.995C>A · VCV4038168

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0858 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0858	likely benign
REVEL	0.365	indeterminate
SaProt	LLR -8.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 2,165 bp · p 0.0031 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0283% Admixed American · 17/59,992 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00116% 17/1,461,648 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: ALG3
Protein: p.Pro332His
Coding: c.995C>A
MANE Select: NM_005787
Type: single nucleotide variant
Location: chr3:184243568 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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ALG3 p.Arg229Cys Uncertain significance ★★ ⚠ same condition
ALG3 p.Arg27Gly Uncertain significance ★★ ⚠ same condition
ALG3 p.Arg378Cys Uncertain significance ★★ ⚠ same condition
ALG3 p.Asn83Ser Uncertain significance ★★ ⚠ same condition
ALG3 p.Cys21Gly Uncertain significance ★★ ⚠ same condition
ALG3 p.Cys21Phe Uncertain significance ★★ ⚠ same condition
ALG3 p.Cys404Trp 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/alg3-p-pro332his (accessed [today's date]).

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