Is COG8 p.Pro508Leu (c.1523C>T) pathogenic?

COG8 p.Pro508Leu (c.1523C>T) is classified Uncertain significance in COG8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-06). AlphaMissense: likely benign (0.2263); Ultra-rare (popmax 0.0495%, mid); Associated with Inborn genetic diseases.

What condition is associated with COG8 p.Pro508Leu (c.1523C>T)?

COG8 p.Pro508Leu (c.1523C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COG8 p.Pro508Leu (c.1523C>T) in the general population?

COG8 p.Pro508Leu (c.1523C>T) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about COG8 p.Pro508Leu (c.1523C>T)?

AlphaMissense predicts likely benign (score 0.2263) — an in-silico prediction, not a clinical call.

COG8 p.Pro508Leu

c.1523C>T · rs533170895 · VCV2614123

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2263 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2263	likely benign
REVEL	0.762	pathogenic-leaning
SaProt	LLR -10.37	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 8,710 bp · p 0.33 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% Middle Eastern · 3/6,062 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.00279% 45/1,614,156 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,021
South Asian	0.00988%	10,121
East Asian	0.00445%	22,448
European (non-Finnish)	0.00254%	39,333
African / African-American	0.00133%	75,034

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.Pro508Leu
Coding: c.1523C>T
MANE Select: NM_032382
dbSNP: rs533170895
Type: single nucleotide variant
Location: chr16:69332773 (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.Pro508Arg Uncertain significance ★ ⚠ same residue
COG8 p.Pro508= Conflicting classifications of pathogenicity ★ 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

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-pro508leu (accessed [today's date]).

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