Is ALG14 p.Ser83Tyr (c.248C>A) pathogenic?

ALG14 p.Ser83Tyr (c.248C>A) is classified Uncertain significance in ALG14 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-24). AlphaMissense: likely benign (0.1456); Very rare (popmax 0.00667%, amr); Associated with congenital myasthenic syndrome 15.

How common is ALG14 p.Ser83Tyr (c.248C>A) in the general population?

ALG14 p.Ser83Tyr (c.248C>A) is very rare (popmax 0.00667%, 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.Ser83Tyr (c.248C>A)?

AlphaMissense predicts likely benign (score 0.1456) — an in-silico prediction, not a clinical call.

ALG14 p.Ser83Tyr

Q: What condition is associated with ALG14 p.Ser83Tyr (c.248C>A)?

ALG14 p.Ser83Tyr (c.248C>A) is associated with congenital myasthenic syndrome 15, intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies, myopathy, epilepsy, and progressive cerebral atrophy (ClinVar).

c.248C>A · rs767402341 · VCV1361709

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1456 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myasthenic syndrome 15

Computational evidence

Protein change
AlphaMissense	0.1456	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -8.94	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 3.2	GERP -0.58, phastCons 0.82
Regional constraint	o/e 1.06	unconstrained · MANE · 90 kb · p 0.32 · regional, not allelic
Overall
CADD	18.82	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 0.00667% Admixed American · 4/59,988 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000434% 7/1,613,750 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,997
African / African-American	0.00267%	37,441
European (non-Finnish)	8.48e-05%	1,179,871

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.Ser83Tyr
Coding: c.248C>A
MANE Select: NM_144988
dbSNP: rs767402341
Type: single nucleotide variant
Location: chr1:95064906 (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

Also linked: intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies myopathy, epilepsy, and progressive cerebral atrophy

For Congenital myasthenic syndrome (Orphanet):

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

Similar variants

ALG14 p.Ala13Ser Uncertain significance ★★ ⚠ same condition
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-ser83tyr (accessed [today's date]).

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