Is COG8 p.Ala458Val (c.1373C>T) pathogenic?

COG8 p.Ala458Val (c.1373C>T) is classified Uncertain significance in COG8 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-06-01). AlphaMissense: likely benign (0.0938); Ultra-rare (popmax 0.0517%, amr); Associated with Inborn genetic diseases.

What condition is associated with COG8 p.Ala458Val (c.1373C>T)?

COG8 p.Ala458Val (c.1373C>T) is associated with Inborn genetic diseases, COG8-congenital disorder of glycosylation (ClinVar).

How common is COG8 p.Ala458Val (c.1373C>T) in the general population?

COG8 p.Ala458Val (c.1373C>T) is ultra-rare (popmax 0.0517%, amr) (gnomAD).

What do computational predictors say about COG8 p.Ala458Val (c.1373C>T)?

AlphaMissense predicts likely benign (score 0.0938) — an in-silico prediction, not a clinical call.

COG8 p.Ala458Val

c.1373C>T · rs149531391 · VCV597493

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0938 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0517%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0938	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -7.44	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 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 8,710 bp · p 0.33 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0517% Admixed American · 31/60,008 alleles

Filtering AF 0.0374% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0325%

Overall 0.00539% 87/1,614,086 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0517%	1,936
Middle Eastern	0.0164%	6,084
African / African-American	0.016%	6,245
Remaining individualsnot grpmax-eligible	0.0112%	8,927
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
European (non-Finnish)	0.00288%	34,707

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: COG8
Protein: p.Ala458Val
Coding: c.1373C>T
MANE Select: NM_032382
dbSNP: rs149531391
Type: single nucleotide variant
Location: chr16:69334561 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.67

Full COG8 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

Also linked: COG8-congenital disorder of glycosylation

Similar variants

COG8 c.1583-1G>A Pathogenic/Likely pathogenic ★★ same condition
COG8 p.Ala16Gly Uncertain significance ★★ ⚠ same condition
COG8 p.Ala2Val Uncertain significance ★★ ⚠ same condition
COG8 p.Ala5Val Uncertain significance ★★ ⚠ same condition
COG8 p.Arg102Cys Uncertain significance ★★ ⚠ same condition
COG8 p.Arg140Gln Uncertain significance ★★ ⚠ same condition
COG8 p.Arg244Lys Uncertain significance ★★ ⚠ same condition
COG8 p.Arg256Trp 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/cog8-p-ala458val (accessed [today's date]).

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