Is CNN2 p.Asp110Glu (c.330C>A) pathogenic?

CNN2 p.Asp110Glu (c.330C>A) is classified Uncertain significance in CNN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely pathogenic (0.9953); Very rare (popmax 0.000339%, nfe).

How common is CNN2 p.Asp110Glu (c.330C>A) in the general population?

CNN2 p.Asp110Glu (c.330C>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CNN2 p.Asp110Glu (c.330C>A)?

AlphaMissense predicts likely pathogenic (score 0.9953) — an in-silico prediction, not a clinical call.

CNN2 p.Asp110Glu

c.330C>A · VCV4837650

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9953 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9953	likely pathogenic · top 8% in CNN2
REVEL	0.636	indeterminate
SaProt	LLR -8.68	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 11 kb · p 0.17 · regional, not allelic
Overall
CADD	24.4	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) · 4/1,180,028 alleles

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

Overall 0.000274% 4/1,460,352 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: CNN2
Protein: p.Asp110Glu
Coding: c.330C>A
MANE Select: NM_004368
Type: single nucleotide variant
Location: chr19:1032636 (GRCh38)
Gene constraint: LOEUF 1.006 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.62 · 1 PDB
Residue 110: the calponin-homology (ch) domain; an α-helix

Full CNN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNN2 p.Ala126Ser Uncertain significance ★ ⚠ same type
CNN2 p.Ala126Thr Uncertain significance ★ ⚠ same type
CNN2 p.Ala161Thr Uncertain significance ★ same type
CNN2 p.Arg227Trp Uncertain significance ★ ⚠ same type
CNN2 p.Arg266Gly Uncertain significance ★ ⚠ same type
CNN2 p.Arg35Cys Uncertain significance ★ ⚠ same type
CNN2 p.Arg35His Uncertain significance ★ ⚠ same type
CNN2 p.Arg77His 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/cnn2-p-asp110glu (accessed [today's date]).

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