Is ALG14 p.His124Pro (c.371A>C) pathogenic?

ALG14 p.His124Pro (c.371A>C) is classified Uncertain significance in ALG14 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-09-12). AlphaMissense: ambiguous (0.5132); Very rare (popmax 8.47e-05%, nfe); Associated with congenital myasthenic syndrome 15.

What condition is associated with ALG14 p.His124Pro (c.371A>C)?

ALG14 p.His124Pro (c.371A>C) is associated with congenital myasthenic syndrome 15 (ClinVar).

How common is ALG14 p.His124Pro (c.371A>C) in the general population?

ALG14 p.His124Pro (c.371A>C) is very rare (popmax 8.47e-05%, nfe) (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.His124Pro (c.371A>C)?

AlphaMissense predicts ambiguous (score 0.5132) — an in-silico prediction, not a clinical call.

ALG14 p.His124Pro

c.371A>C · rs1553228218 · VCV542123

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5132 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

congenital myasthenic syndrome 15

Computational evidence

Protein change
AlphaMissense	0.5132	ambiguous
REVEL	0.23	benign-leaning
SaProt	LLR -15.44	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.59	GERP -3.8
Regional constraint	o/e 1.06	unconstrained · MANE · 90 kb · p 0.32 · regional, not allelic
Overall
CADD	15.13	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 8.47e-05% European (non-Finnish) · 1/1,179,962 alleles

Overall 0.000658% 1/152,022 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: ALG14
Protein: p.His124Pro
Coding: c.371A>C
MANE Select: NM_144988
dbSNP: rs1553228218
Type: single nucleotide variant
Location: chr1:95027178 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.06
Residue 124: a UniProt-annotated variant site (in cms15)

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.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
ALG14 p.His190Gln 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-his124pro (accessed [today's date]).

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