Is ALG1 p.Leu273Ile (c.817C>A) pathogenic?

ALG1 p.Leu273Ile (c.817C>A) is classified Uncertain significance in ALG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-24). AlphaMissense: likely benign (0.1058); Very rare (popmax 0.00534%, afr).

How common is ALG1 p.Leu273Ile (c.817C>A) in the general population?

ALG1 p.Leu273Ile (c.817C>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about ALG1 p.Leu273Ile (c.817C>A)?

AlphaMissense predicts likely benign (score 0.1058) — an in-silico prediction, not a clinical call.

ALG1 p.Leu273Ile

c.817C>A · VCV3900223

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1058 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1058	likely benign
REVEL	0.233	benign-leaning
SaProt	LLR -7.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.76	GERP 0.48
Regional constraint	o/e 1.27	unconstrained · MANE · 13 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	8.461	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 0.00534% African / African-American · 4/74,890 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,612,044 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.Leu273Ile
Coding: c.817C>A
MANE Select: NM_019109
Type: single nucleotide variant
Location: chr16:5078833 (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 p.Leu273Val Uncertain significance ★★ ⚠ same residue
ALG1 p.Leu273= Likely benign ★ same residue
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

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-leu273ile (accessed [today's date]).

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