Is CNN1 p.Pro231Leu (c.692C>T) pathogenic?

CNN1 p.Pro231Leu (c.692C>T) is classified Uncertain significance in CNN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: likely benign (0.1414); Very rare (popmax 0.00896%, eas).

How common is CNN1 p.Pro231Leu (c.692C>T) in the general population?

CNN1 p.Pro231Leu (c.692C>T) is very rare (popmax 0.00896%, eas) (gnomAD).

What do computational predictors say about CNN1 p.Pro231Leu (c.692C>T)?

AlphaMissense predicts likely benign (score 0.1414) — an in-silico prediction, not a clinical call.

CNN1 p.Pro231Leu

c.692C>T · VCV4004290

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1414 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00896%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1414	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -10.87	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.73, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 11 kb · p 1.5e-05 · regional, not allelic
Overall
CADD	22.1	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 0.00896% East Asian · 4/44,630 alleles

Filtering AF 0.00348% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.0015% 24/1,604,490 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00896%	11,158
African / African-American	0.00803%	12,458
Admixed American	0.00671%	14,898
Remaining individualsnot grpmax-eligible	0.00161%	61,984
Finnishnot grpmax-eligible	0.00157%	63,810
South Asian	0.0011%	90,510
European (non-Finnish)	0.000597%	167,568

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.Pro231Leu
Coding: c.692C>T
MANE Select: NM_001299
Type: single nucleotide variant
Location: chr19:11549593 (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.Val243Ile Uncertain significance ★★ ⚠ same type
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

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-pro231leu (accessed [today's date]).

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