Is COG8 p.Arg481His (c.1442G>A) pathogenic?

COG8 p.Arg481His (c.1442G>A) is classified Uncertain significance in COG8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-28). AlphaMissense: likely benign (0.091); Ultra-rare (popmax 0.0111%, eas); Associated with Inborn genetic diseases.

What condition is associated with COG8 p.Arg481His (c.1442G>A)?

COG8 p.Arg481His (c.1442G>A) is associated with Inborn genetic diseases (ClinVar).

How common is COG8 p.Arg481His (c.1442G>A) in the general population?

COG8 p.Arg481His (c.1442G>A) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about COG8 p.Arg481His (c.1442G>A)?

AlphaMissense predicts likely benign (score 0.091) — an in-silico prediction, not a clinical call.

COG8 p.Arg481His

c.1442G>A · rs1387014270 · VCV3147140

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.091 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.091	likely benign
REVEL	0.364	indeterminate
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 8,710 bp · p 0.33 · regional, not allelic
Overall
CADD	28.4	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 0.0111% East Asian · 5/44,900 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00118% 19/1,614,058 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,980
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,802
South Asian	0.00329%	30,362
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00133%	74,914
European (non-Finnish)	0.000593%	168,578

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.Arg481His
Coding: c.1442G>A
MANE Select: NM_032382
dbSNP: rs1387014270
Type: single nucleotide variant
Location: chr16:69332854 (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

Similar variants

COG8 p.Arg481= Likely benign ★ same residue
COG8 p.Ala16Gly Uncertain significance ★★ ⚠ same condition
COG8 p.Ala458Val Uncertain significance ★★ ⚠ same condition
COG8 p.Arg102Cys Uncertain significance ★★ ⚠ same condition
COG8 p.Arg256Trp Uncertain significance ★★ ⚠ same condition
COG8 p.Asn440Ser Uncertain significance ★★ ⚠ same condition
COG8 p.Glu311Asp Uncertain significance ★★ ⚠ same condition
COG8 p.Glu64Asp 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-arg481his (accessed [today's date]).

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