Is COG5 p.Pro478Ser (c.1432C>T) pathogenic?

COG5 p.Pro478Ser (c.1432C>T) is classified Uncertain significance in COG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-01). AlphaMissense: likely pathogenic (0.8121); Very rare (popmax 0.00133%, afr); Associated with COG5-congenital disorder of glycosylation.

What condition is associated with COG5 p.Pro478Ser (c.1432C>T)?

COG5 p.Pro478Ser (c.1432C>T) is associated with COG5-congenital disorder of glycosylation (ClinVar).

How common is COG5 p.Pro478Ser (c.1432C>T) in the general population?

COG5 p.Pro478Ser (c.1432C>T) is very rare (popmax 0.00133%, afr) (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.Pro478Ser (c.1432C>T)?

AlphaMissense predicts likely pathogenic (score 0.8121) — an in-silico prediction, not a clinical call.

COG5 p.Pro478Ser

c.1432C>T · rs1279772707 · VCV1429774

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8121 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

COG5-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.8121	likely pathogenic
REVEL	0.517	indeterminate
SaProt	LLR -12.22	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 360 kb · p 0.0042 · regional, not allelic
Overall
CADD	27.1	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 P509S vs ClinVar P478S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,022 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000558% 9/1,613,988 alleles · very rare exomes 9/1,461,744 · genomes 0/152,244 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,498
African / African-Americangrpmax	0.00133%	75,022
European (non-Finnish)	0.000593%	168,563

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: COG5
Protein: p.Pro478Ser
Coding: c.1432C>T
MANE Select: NM_006348
dbSNP: rs1279772707
Type: single nucleotide variant
Location: chr7:107283614 (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

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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
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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-pro478ser (accessed [today's date]).

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