Is CNN1 p.Val243Ile (c.727G>A) pathogenic?

CNN1 p.Val243Ile (c.727G>A) is classified Uncertain significance in CNN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-14). AlphaMissense: likely benign (0.0669); Ultra-rare (popmax 0.0427%, afr).

How common is CNN1 p.Val243Ile (c.727G>A) in the general population?

CNN1 p.Val243Ile (c.727G>A) is ultra-rare (popmax 0.0427%, afr) (gnomAD).

What do computational predictors say about CNN1 p.Val243Ile (c.727G>A)?

AlphaMissense predicts likely benign (score 0.0669) — an in-silico prediction, not a clinical call.

CNN1 p.Val243Ile

c.727G>A · rs369315192 · VCV2469975

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0669 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0427%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0669	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -6.25	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 3.9	GERP -1.9, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 11 kb · p 1.5e-05 · regional, not allelic
Overall
CADD	15.8	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 0.0427% African / African-American · 32/74,908 alleles

Filtering AF 0.031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0271%

Overall 0.00205% 33/1,613,208 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0427%	2,341
East Asian	0.00223%	44,864

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: CNN1
Protein: p.Val243Ile
Coding: c.727G>A
MANE Select: NM_001299
dbSNP: rs369315192
Type: single nucleotide variant
Location: chr19:11549628 (GRCh38)
Gene constraint: LOEUF 0.811 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.06 · 1 PDB

Full CNN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNN1 p.Ala145Thr Uncertain significance ★ ⚠ same type
CNN1 p.Ala290Val Uncertain significance ★ ⚠ same type
CNN1 p.Ala297Thr Uncertain significance ★ ⚠ same type
CNN1 p.Arg150Gln Uncertain significance ★ ⚠ same type
CNN1 p.Arg158Lys Uncertain significance ★ ⚠ same type
CNN1 p.Arg185Gln Uncertain significance ★ ⚠ same type
CNN1 p.Arg185Trp Uncertain significance ★ ⚠ same type
CNN1 p.Arg186Cys 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/cnn1-p-val243ile (accessed [today's date]).

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