Is COG5 p.Ala738Pro (c.2212G>C) pathogenic?

COG5 p.Ala738Pro (c.2212G>C) is classified Uncertain significance in COG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-06). AlphaMissense: ambiguous (0.4482); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with COG5 p.Ala738Pro (c.2212G>C)?

COG5 p.Ala738Pro (c.2212G>C) is associated with Inborn genetic diseases (ClinVar).

How common is COG5 p.Ala738Pro (c.2212G>C) in the general population?

COG5 p.Ala738Pro (c.2212G>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about COG5 p.Ala738Pro (c.2212G>C)?

AlphaMissense predicts ambiguous (score 0.4482) — an in-silico prediction, not a clinical call.

COG5 p.Ala738Pro

c.2212G>C · rs756618451 · VCV2557851

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4482 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4482	ambiguous
REVEL	0.227	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -0.97, phastCons 0.47
Regional constraint	o/e 1.09	unconstrained · MANE · 360 kb · p 0.0042 · regional, not allelic
Overall
CADD	18.86	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 A748P vs ClinVar A738P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,892 alleles

Overall 0.000657% 1/152,140 alleles · very rare

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.Ala738Pro
Coding: c.2212G>C
MANE Select: NM_006348
dbSNP: rs756618451
Type: single nucleotide variant
Location: chr7:107211182 (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.Ala738Ser Uncertain significance ★ ⚠ same residue
COG5 p.Ala738= Likely benign ★ 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

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-ala738pro (accessed [today's date]).

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