Is ALG14 p.Asp74Glu (c.222T>A) pathogenic?

ALG14 p.Asp74Glu (c.222T>A) is classified Uncertain significance in ALG14 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-22). AlphaMissense: likely pathogenic (0.9789); Very rare (popmax 0.00161%, nfe).

How common is ALG14 p.Asp74Glu (c.222T>A) in the general population?

ALG14 p.Asp74Glu (c.222T>A) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about ALG14 p.Asp74Glu (c.222T>A)?

AlphaMissense predicts likely pathogenic (score 0.9789) — an in-silico prediction, not a clinical call.

ALG14 p.Asp74Glu

c.222T>A · rs2525847547 · VCV2506613

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9789 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9789	likely pathogenic · top 8% in ALG14
REVEL	0.704	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 3	GERP 0.2, phastCons 0.99
Regional constraint	o/e 1.06	unconstrained · MANE · 90 kb · p 0.32 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00161% European (non-Finnish) · 19/1,179,932 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.0013% 19/1,461,724 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.Asp74Glu
Coding: c.222T>A
MANE Select: NM_144988
dbSNP: rs2525847547
Type: single nucleotide variant
Location: chr1:95064932 (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

Similar variants

ALG14 p.Asp74Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
ALG14 p.Ala13Ser Uncertain significance ★★ ⚠ same type
ALG14 p.Arg104Gln Uncertain significance ★★ ⚠ same type
ALG14 p.Arg109Gln Uncertain significance ★★ ⚠ same type
ALG14 p.Arg109Trp Uncertain significance ★★ ⚠ same type
ALG14 p.Asn61Asp Uncertain significance ★★ ⚠ same type
ALG14 p.Asn61Ser Uncertain significance ★★ ⚠ same type
ALG14 p.Asn82Ser Uncertain significance ★★ ⚠ same type

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-asp74glu (accessed [today's date]).

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