Is CNN2 p.Ala126Thr (c.376G>A) pathogenic?

CNN2 p.Ala126Thr (c.376G>A) is classified Uncertain significance in CNN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: ambiguous (0.4207); Very rare (popmax 0.00223%, eas).

How common is CNN2 p.Ala126Thr (c.376G>A) in the general population?

CNN2 p.Ala126Thr (c.376G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CNN2 p.Ala126Thr (c.376G>A)?

AlphaMissense predicts ambiguous (score 0.4207) — an in-silico prediction, not a clinical call.

CNN2 p.Ala126Thr

c.376G>A · VCV4230818

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4207 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4207	ambiguous
REVEL	0.768	pathogenic-leaning
SaProt	LLR -10.98	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 1.6, 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 0.00223% East Asian · 1/44,820 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000869% 14/1,610,410 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,820
Admixed American	0.00167%	59,850
Remaining individualsnot grpmax-eligible	0.0016%	62,318
South Asian	0.0011%	90,878
European (non-Finnish)	0.000848%	117,919

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.Ala126Thr
Coding: c.376G>A
MANE Select: NM_004368
Type: single nucleotide variant
Location: chr19:1032682 (GRCh38)
Gene constraint: LOEUF 1.006 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.62 · 1 PDB
Residue 126: 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 residue
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
CNN2 p.Asn256Ile 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-ala126thr (accessed [today's date]).

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