Is ALG14 p.Asp74Asn (c.220G>A) pathogenic?

ALG14 p.Asp74Asn (c.220G>A) is classified Conflicting classifications of pathogenicity in ALG14 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-19). AlphaMissense: likely pathogenic (0.9547); Ultra-rare (popmax 0.0294%, nfe); Associated with myopathy, epilepsy, and progressive cerebral atrophy.

What condition is associated with ALG14 p.Asp74Asn (c.220G>A)?

ALG14 p.Asp74Asn (c.220G>A) is associated with myopathy, epilepsy, and progressive cerebral atrophy, congenital myasthenic syndrome 15, congenital myopathy (ClinVar).

How common is ALG14 p.Asp74Asn (c.220G>A) in the general population?

ALG14 p.Asp74Asn (c.220G>A) is ultra-rare (popmax 0.0294%, nfe) (gnomAD).

What do computational predictors say about ALG14 p.Asp74Asn (c.220G>A)?

AlphaMissense predicts likely pathogenic (score 0.9547) — an in-silico prediction, not a clinical call.

ALG14 p.Asp74Asn

c.220G>A · rs769114543 · VCV389968

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9547 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0294%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myopathy, epilepsy, and progressive cerebral atrophy

Computational evidence

Protein change
AlphaMissense	0.9547	likely pathogenic
REVEL	0.697	pathogenic-leaning
SaProt	LLR -12.18	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.4, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 90 kb · p 0.32 · regional, not allelic
Overall
CADD	29.5	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 0.0294% European (non-Finnish) · 347/1,179,758 alleles

Filtering AF 0.0268% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.0229% 369/1,613,706 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0294%	3,400
Admixed American	0.015%	6,666
African / African-American	0.0107%	9,365
Remaining individualsnot grpmax-eligible	0.008%	12,495

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.Asp74Asn
Coding: c.220G>A
MANE Select: NM_144988
dbSNP: rs769114543
Type: single nucleotide variant
Location: chr1:95064934 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.06
Residue 74: a UniProt-annotated variant site (in mepca; decreased function in dolichol-linked oligosaccharide biosynthetic process)

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

Disease context

myopathy, epilepsy, and progressive cerebral atrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myasthenic syndrome 15 congenital myopathy

Similar variants

ALG14 p.Asp74Glu Uncertain significance ★ ⚠ same residue
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

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-asp74asn (accessed [today's date]).

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