Is ALG9 p.Ala421Pro (c.1261G>C) pathogenic?

ALG9 p.Ala421Pro (c.1261G>C) is classified Uncertain significance in ALG9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-25). AlphaMissense: likely pathogenic (0.7635); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ALG9 p.Ala421Pro (c.1261G>C)?

ALG9 p.Ala421Pro (c.1261G>C) is associated with Inborn genetic diseases (ClinVar).

How common is ALG9 p.Ala421Pro (c.1261G>C) in the general population?

ALG9 p.Ala421Pro (c.1261G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALG9 p.Ala421Pro (c.1261G>C)?

AlphaMissense predicts likely pathogenic (score 0.7635) — an in-silico prediction, not a clinical call.

ALG9 p.Ala421Pro

c.1261G>C · rs782251015 · VCV3111426

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7635 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7635	likely pathogenic
REVEL	0.493	indeterminate
SaProt	LLR -5.60	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 54 kb · p 0.028 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A414P vs ClinVar A421P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ALG9
Protein: p.Ala421Pro
Coding: c.1261G>C
MANE Select: NM_024740
dbSNP: rs782251015
Type: single nucleotide variant
Location: chr11:111838312 (GRCh38)
Gene constraint: LOEUF 0.853 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.35 · 2 PDB

Full ALG9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ALG9 p.Arg607Gln Uncertain significance ★★ ⚠ same condition
ALG9 p.Gln526Glu Uncertain significance ★★ ⚠ same condition
ALG9 p.Ile130Val Uncertain significance ★★ ⚠ same condition
ALG9 p.Ser17Thr Uncertain significance ★★ ⚠ same condition
ALG9 p.Arg42Trp Uncertain significance ★ ⚠ same condition
ALG9 p.Arg517Trp Uncertain significance ★ ⚠ same condition
ALG9 p.Arg584Trp Conflicting classifications of pathogenicity ★ ⚠ same condition
ALG9 p.Gly37Asp 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/alg9-p-ala421pro (accessed [today's date]).

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