Is ALG2 p.Leu407Phe (c.1219C>T) pathogenic?

ALG2 p.Leu407Phe (c.1219C>T) is classified Uncertain significance in ALG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-03). AlphaMissense: likely benign (0.3341); Ultra-rare (popmax 0.0493%, mid); Associated with Inborn genetic diseases.

What condition is associated with ALG2 p.Leu407Phe (c.1219C>T)?

ALG2 p.Leu407Phe (c.1219C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ALG2 p.Leu407Phe (c.1219C>T) in the general population?

ALG2 p.Leu407Phe (c.1219C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about ALG2 p.Leu407Phe (c.1219C>T)?

AlphaMissense predicts likely benign (score 0.3341) — an in-silico prediction, not a clinical call.

ALG2 p.Leu407Phe

c.1219C>T · VCV3284166

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3341 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3341	likely benign
REVEL	0.629	indeterminate
SaProt	LLR -7.70	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.83, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 3,957 bp · p 0.038 · regional, not allelic
Overall
CADD	23.4	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 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00715%

Overall 0.00415% 67/1,614,128 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
European (non-Finnish)	0.00517%	19,345
East Asian	0.00223%	44,908
Remaining individualsnot grpmax-eligible	0.0016%	62,490
South Asian	0.0011%	91,094

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: ALG2
Protein: p.Leu407Phe
Coding: c.1219C>T
MANE Select: NM_033087
Type: single nucleotide variant
Location: chr9:99217966 (GRCh38)
Gene constraint: LOEUF 1.408 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.03

Full ALG2 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

ALG2 p.Ala71Gly Uncertain significance ★★ ⚠ same condition
ALG2 p.Arg393Gly Uncertain significance ★★ ⚠ same condition
ALG2 p.Arg7Trp Uncertain significance ★★ ⚠ same condition
ALG2 p.Asp148Gly Uncertain significance ★★ ⚠ same condition
ALG2 p.Cys120Tyr Uncertain significance ★★ ⚠ same condition
ALG2 p.Gln338His Uncertain significance ★★ ⚠ same condition
ALG2 p.Gln406His Uncertain significance ★★ ⚠ same condition
ALG2 p.Glu235Lys 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/alg2-p-leu407phe (accessed [today's date]).

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