Is COG5 p.Leu320Pro (c.959T>C) pathogenic?

COG5 p.Leu320Pro (c.959T>C) is classified Uncertain significance in COG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-11-15). AlphaMissense: likely pathogenic (0.9932); Absent from gnomAD v4.1; Associated with COG5-congenital disorder of glycosylation.

What condition is associated with COG5 p.Leu320Pro (c.959T>C)?

COG5 p.Leu320Pro (c.959T>C) is associated with COG5-congenital disorder of glycosylation (ClinVar).

How common is COG5 p.Leu320Pro (c.959T>C) in the general population?

COG5 p.Leu320Pro (c.959T>C) is absent from gnomAD v4.1 (gnomAD).

How is COG5-CDG inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about COG5 p.Leu320Pro (c.959T>C)?

AlphaMissense predicts likely pathogenic (score 0.9932) — an in-silico prediction, not a clinical call.

COG5 p.Leu320Pro

c.959T>C · rs1584729488 · VCV800520

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9932 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

COG5-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.9932	likely pathogenic · top 1% in COG5
REVEL	0.848	moderately pathogenic-leaning
SaProt	LLR -16.60	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 11	GERP 2.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 360 kb · p 0.0042 · regional, not allelic
Overall
CADD	28.5	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L351P vs ClinVar L320P) — 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: COG5
Protein: p.Leu320Pro
Coding: c.959T>C
MANE Select: NM_006348
dbSNP: rs1584729488
Type: single nucleotide variant
Location: chr7:107362100 (GRCh38)
Gene constraint: LOEUF 1.026 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37

Full COG5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

COG5-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For COG5-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

COG5 p.Leu320Ile Uncertain significance ★★ ⚠ same residue
COG5 c.1475+1G>A Likely pathogenic ★★ same condition
COG5 c.2295+2T>C Pathogenic/Likely pathogenic ★★ same condition
COG5 p.Arg205Ter Pathogenic ★★ same condition
COG5 p.Arg283Ter Pathogenic ★★ same condition
COG5 p.Arg461Ter Pathogenic/Likely pathogenic ★★ same condition
COG5 p.Arg690Ter Pathogenic/Likely pathogenic ★★ same condition
COG5 p.Arg708Ter Pathogenic/Likely pathogenic ★★ 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/cog5-p-leu320pro (accessed [today's date]).

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