Is COG2 p.Ser375Asn (c.1124G>A) pathogenic?

COG2 p.Ser375Asn (c.1124G>A) is classified Uncertain significance in COG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-16). AlphaMissense: likely benign (0.0749); Ultra-rare (popmax 0.0154%, sas).

How common is COG2 p.Ser375Asn (c.1124G>A) in the general population?

COG2 p.Ser375Asn (c.1124G>A) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about COG2 p.Ser375Asn (c.1124G>A)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

COG2 p.Ser375Asn

c.1124G>A · VCV3268465

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -8.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 4.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 51 kb · p 0.037 · regional, not allelic
Overall
CADD	18.06	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 0.0154% South Asian · 14/91,062 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.000868% 14/1,613,456 alleles · ultra-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.Ser375Asn
Coding: c.1124G>A
MANE Select: NM_007357
Type: single nucleotide variant
Location: chr1:230679010 (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.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
COG2 p.Arg39Trp 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-ser375asn (accessed [today's date]).

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