Is COG5 p.Ile334Val (c.1000A>G) pathogenic?

COG5 p.Ile334Val (c.1000A>G) is classified Benign in COG5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0609); Common (popmax 7.56%, afr) — too common for a highly-penetrant pathogenic allele; Associated with COG5-congenital disorder of glycosylation.

What condition is associated with COG5 p.Ile334Val (c.1000A>G)?

COG5 p.Ile334Val (c.1000A>G) is associated with COG5-congenital disorder of glycosylation (ClinVar).

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.Ile334Val (c.1000A>G)?

AlphaMissense predicts likely benign (score 0.0609) — an in-silico prediction, not a clinical call.

COG5 p.Ile334Val

Q: How common is COG5 p.Ile334Val (c.1000A>G) in the general population?

COG5 p.Ile334Val (c.1000A>G) is common (popmax 7.56%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1000A>G · rs34087251 · VCV358464

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0609 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.56%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

COG5-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.0609	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -4.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.14	GERP -1.7, phastCons 0.032
Regional constraint	o/e 1.09	unconstrained · MANE · 360 kb · p 0.0042 · regional, not allelic
Overall
CADD	6.305	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 I365V vs ClinVar I334V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.56% African / African-American · 5,659/74,894 alleles

Filtering AF 7.39% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.32%

Overall 5.23% 83,978/1,605,418 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.56%	13
Amishnot grpmax-eligible	6.25%	16
European (non-Finnish)	5.67%	18
Middle Eastern	5.29%	19
Remaining individualsnot grpmax-eligible	5.09%	20
Ashkenazi Jewishnot grpmax-eligible	4.49%	22
Finnishnot grpmax-eligible	4.36%	23
Admixed American	2.82%	35
South Asian	2.67%	37
East Asian	0.0446%	2,243

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.Ile334Val
Coding: c.1000A>G
MANE Select: NM_006348
dbSNP: rs34087251
Type: single nucleotide variant
Location: chr7:107362059 (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 c.1475+1G>A Likely pathogenic ★★ same condition
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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
COG5 p.Met1Arg 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-ile334val (accessed [today's date]).

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