Is ALG14 p.Leu37Phe (c.109C>T) pathogenic?

ALG14 p.Leu37Phe (c.109C>T) is classified Uncertain significance in ALG14 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-02). AlphaMissense: likely benign (0.164); Very rare (popmax 0.00167%, amr); Associated with congenital myasthenic syndrome 15.

What condition is associated with ALG14 p.Leu37Phe (c.109C>T)?

ALG14 p.Leu37Phe (c.109C>T) is associated with congenital myasthenic syndrome 15 (ClinVar).

How common is ALG14 p.Leu37Phe (c.109C>T) in the general population?

ALG14 p.Leu37Phe (c.109C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Congenital myasthenic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ALG14 p.Leu37Phe (c.109C>T)?

AlphaMissense predicts likely benign (score 0.164) — an in-silico prediction, not a clinical call.

ALG14 p.Leu37Phe

c.109C>T · rs1212603713 · VCV1408192

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.164 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 15

Computational evidence

Protein change
AlphaMissense	0.164	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -7.22	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 1.5	GERP -1.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 90 kb · p 0.32 · regional, not allelic
Overall
CADD	16.72	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 0.00167% Admixed American · 1/60,028 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000342% 5/1,461,890 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,028
European (non-Finnish)	0.000339%	295,010

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: ALG14
Protein: p.Leu37Phe
Coding: c.109C>T
MANE Select: NM_144988
dbSNP: rs1212603713
Type: single nucleotide variant
Location: chr1:95072790 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.06

Full ALG14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital myasthenic syndrome 15 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital myasthenic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

ALG14 p.Leu37= Likely benign ★ same residue
ALG14 p.Arg104Gln Uncertain significance ★★ ⚠ same condition
ALG14 p.Arg109Gln Uncertain significance ★★ ⚠ same condition
ALG14 p.Asn61Asp Uncertain significance ★★ ⚠ same condition
ALG14 p.Asn61Ser Uncertain significance ★★ ⚠ same condition
ALG14 p.Asn82Ser Uncertain significance ★★ ⚠ same condition
ALG14 p.Glu110Lys Uncertain significance ★★ same condition
ALG14 p.Glu179Lys 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/alg14-p-leu37phe (accessed [today's date]).

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