Is ALG11 p.Pro280Leu (c.839C>T) pathogenic?

ALG11 p.Pro280Leu (c.839C>T) is classified Uncertain significance in ALG11 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-26). AlphaMissense: likely pathogenic (0.9073); Absent from gnomAD v4.1.

How common is ALG11 p.Pro280Leu (c.839C>T) in the general population?

ALG11 p.Pro280Leu (c.839C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALG11 p.Pro280Leu (c.839C>T)?

AlphaMissense predicts likely pathogenic (score 0.9073) — an in-silico prediction, not a clinical call.

ALG11 p.Pro280Leu

c.839C>T · rs2547344143 · VCV3252903

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9073 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9073	likely pathogenic
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -15.06	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.068 · regional, not allelic
Overall
CADD	31.0	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

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: ALG11
Protein: p.Pro280Leu
Coding: c.839C>T
MANE Select: NM_001004127
dbSNP: rs2547344143
Type: single nucleotide variant
Location: chr13:52024569 (GRCh38)
Gene constraint: LOEUF 0.908 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.40

Full ALG11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALG11 c.45-2A>T Likely pathogenic ★★ same type
ALG11 p.Arg468Cys Likely pathogenic ★★ ⚠ same type
ALG11 p.Arg468His Likely pathogenic ★★ same type
ALG11 p.Met1Val Likely pathogenic ★★ same type
ALG11 c.*540T>A Uncertain significance ★★ ⚠ same type
ALG11 p.Arg136Cys Uncertain significance ★★ same type
ALG11 p.Arg15Thr Uncertain significance ★★ ⚠ same type
ALG11 p.Arg346His 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/alg11-p-pro280leu (accessed [today's date]).

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