Is COG2 p.Pro12Leu (c.35C>T) pathogenic?

COG2 p.Pro12Leu (c.35C>T) is classified Uncertain significance in COG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-12). AlphaMissense: ambiguous (0.4059); Very rare (popmax 0.000339%, nfe).

How common is COG2 p.Pro12Leu (c.35C>T) in the general population?

COG2 p.Pro12Leu (c.35C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about COG2 p.Pro12Leu (c.35C>T)?

AlphaMissense predicts ambiguous (score 0.4059) — an in-silico prediction, not a clinical call.

COG2 p.Pro12Leu

c.35C>T · VCV4655374

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4059 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4059	ambiguous
REVEL	0.172	moderately benign-leaning
SaProt	LLR -9.28	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 51 kb · p 0.037 · regional, not allelic
Overall
CADD	29.8	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 0.000339% European (non-Finnish) · 4/1,179,660 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,460,838 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: COG2
Protein: p.Pro12Leu
Coding: c.35C>T
MANE Select: NM_007357
Type: single nucleotide variant
Location: chr1:230642641 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.38

Full COG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COG2 p.Pro12= Likely benign ★ same residue
COG2 p.Ala160Val Uncertain significance ★★ ⚠ same type
COG2 p.Ala339Pro Uncertain significance ★★ ⚠ same type
COG2 p.Arg138Gln Uncertain significance ★★ ⚠ same type
COG2 p.Arg241Gln Uncertain significance ★★ ⚠ same type
COG2 p.Arg356Gln Uncertain significance ★★ ⚠ same type
COG2 p.Arg356Trp Uncertain significance ★★ ⚠ same type
COG2 p.Arg39Gln Uncertain significance ★★ ⚠ same type

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/cog2-p-pro12leu (accessed [today's date]).

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