Is ALG1 p.Gly321Arg (c.961G>C) pathogenic?

ALG1 p.Gly321Arg (c.961G>C) is classified Uncertain significance in ALG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-31). AlphaMissense: likely pathogenic (0.9727); Very rare (popmax 0.0011%, sas).

How common is ALG1 p.Gly321Arg (c.961G>C) in the general population?

ALG1 p.Gly321Arg (c.961G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ALG1 p.Gly321Arg (c.961G>C)?

AlphaMissense predicts likely pathogenic (score 0.9727) — an in-silico prediction, not a clinical call.

ALG1 p.Gly321Arg

c.961G>C · rs1367327454 · VCV1699574

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9727 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9727	likely pathogenic · top 6% in ALG1
REVEL	0.946	strongly pathogenic-leaning
SaProt	LLR -16.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.93	donor loss · deltas
Pangolin	Δ0.81	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.8	GERP 1.8, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 13 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	35.0	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 0.0011% South Asian · 1/90,994 alleles

Overall 6.85e-05% 1/1,459,560 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: ALG1
Protein: p.Gly321Arg
Coding: c.961G>C
MANE Select: NM_019109
dbSNP: rs1367327454
Type: single nucleotide variant
Location: chr16:5079807 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.24

Full ALG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALG1 c.1187+1G>A Pathogenic/Likely pathogenic ★★ same type
ALG1 c.1187+2T>C Pathogenic ★★ same type
ALG1 c.1188-2A>G Pathogenic/Likely pathogenic ★★ same type
ALG1 c.209-2A>G Likely pathogenic ★★ same type
ALG1 c.539+1G>A Pathogenic/Likely pathogenic ★★ same type
ALG1 c.630-2A>G Likely pathogenic ★★ same type
ALG1 c.863-2A>G Likely pathogenic ★★ same type
ALG1 c.961+1G>A 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/alg1-p-gly321arg (accessed [today's date]).

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