Is ALG1 p.Pro324Leu (c.971C>T) pathogenic?

ALG1 p.Pro324Leu (c.971C>T) is classified Uncertain significance in ALG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: ambiguous (0.3742); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with ALG1 p.Pro324Leu (c.971C>T)?

ALG1 p.Pro324Leu (c.971C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ALG1 p.Pro324Leu (c.971C>T) in the general population?

ALG1 p.Pro324Leu (c.971C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ALG1 p.Pro324Leu (c.971C>T)?

AlphaMissense predicts ambiguous (score 0.3742) — an in-silico prediction, not a clinical call.

ALG1 p.Pro324Leu

c.971C>T · VCV4574599

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3742	ambiguous
REVEL	0.71	pathogenic-leaning
SaProt	LLR -11.63	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 13 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,926 alleles

Overall 0.000138% 2/1,444,116 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
African / African-Americangrpmax	0.00133%	74,926

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro324Leu
Coding: c.971C>T
MANE Select: NM_019109
Type: single nucleotide variant
Location: chr16:5080955 (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

Disease context

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

Similar variants

ALG1 p.Pro324Ala Uncertain significance ★ ⚠ same residue
ALG1 p.Ala360Val Pathogenic/Likely pathogenic ★★ same condition
ALG1 p.Gln342Pro Pathogenic/Likely pathogenic ★★ ⚠ same condition
ALG1 p.Ala278Thr Uncertain significance ★★ ⚠ same condition
ALG1 p.Arg257Gln Uncertain significance ★★ ⚠ same condition
ALG1 p.Asn311Lys Uncertain significance ★★ ⚠ same condition
ALG1 p.Asn80His Uncertain significance ★★ ⚠ same condition
ALG1 p.Asp252Glu 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/alg1-p-pro324leu (accessed [today's date]).

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