Is COG5 p.Val702Met (c.2104G>A) pathogenic?

COG5 p.Val702Met (c.2104G>A) is classified Uncertain significance in COG5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-30). AlphaMissense: likely benign (0.2577); Very rare (popmax 0.00549%, sas); Associated with Inborn genetic diseases.

What condition is associated with COG5 p.Val702Met (c.2104G>A)?

COG5 p.Val702Met (c.2104G>A) is associated with Inborn genetic diseases (ClinVar).

How common is COG5 p.Val702Met (c.2104G>A) in the general population?

COG5 p.Val702Met (c.2104G>A) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about COG5 p.Val702Met (c.2104G>A)?

AlphaMissense predicts likely benign (score 0.2577) — an in-silico prediction, not a clinical call.

COG5 p.Val702Met

c.2104G>A · rs398124222 · VCV95373

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2577 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2577	likely benign
REVEL	0.277	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 360 kb · p 0.0042 · regional, not allelic
Overall
CADD	22.9	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V712M vs ClinVar V702M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% South Asian · 5/91,012 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.00186% 30/1,610,076 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,202
Remaining individualsnot grpmax-eligible	0.00481%	20,797
African / African-American	0.00267%	37,490
European (non-Finnish)	0.0017%	58,818

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.Val702Met
Coding: c.2104G>A
MANE Select: NM_006348
dbSNP: rs398124222
Type: single nucleotide variant
Location: chr7:107230679 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COG5 p.Val702Leu Uncertain significance ★★ ⚠ same residue
COG5 p.Tyr416Ter Pathogenic ★★ same condition
COG5 c.-25C>A Uncertain significance ★★ ⚠ same condition
COG5 p.Ala15Gly Uncertain significance ★★ ⚠ same condition
COG5 p.Ala20Val Uncertain significance ★★ ⚠ same condition
COG5 p.Ala263Thr Uncertain significance ★★ ⚠ same condition
COG5 p.Ala409Thr Uncertain significance ★★ ⚠ same condition
COG5 p.Ala62Thr 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/cog5-p-val702met (accessed [today's date]).

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