Is CNN1 p.Arg185Trp (c.553C>T) pathogenic?

CNN1 p.Arg185Trp (c.553C>T) is classified Uncertain significance in CNN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-27). AlphaMissense: likely pathogenic (0.9061); Ultra-rare (popmax 0.0183%, nfe).

How common is CNN1 p.Arg185Trp (c.553C>T) in the general population?

CNN1 p.Arg185Trp (c.553C>T) is ultra-rare (popmax 0.0183%, nfe) (gnomAD).

What do computational predictors say about CNN1 p.Arg185Trp (c.553C>T)?

AlphaMissense predicts likely pathogenic (score 0.9061) — an in-silico prediction, not a clinical call.

CNN1 p.Arg185Trp

c.553C>T · rs201786372 · VCV3146524

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9061 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9061	likely pathogenic
REVEL	0.43	indeterminate
SaProt	LLR -11.54	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -0.54, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 11 kb · p 1.5e-05 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0183% European (non-Finnish) · 216/1,179,984 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0155%

Overall 0.0154% 249/1,614,022 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0183%	5,463
Remaining individualsnot grpmax-eligible	0.0176%	5,682
African / African-American	0.016%	6,250
Finnishnot grpmax-eligible	0.0109%	9,147
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
East Asian	0.00223%	44,872
Admixed American	0.00167%	59,992

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.Arg185Trp
Coding: c.553C>T
MANE Select: NM_001299
dbSNP: rs201786372
Type: single nucleotide variant
Location: chr19:11549374 (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.Arg185Gln Uncertain significance ★ ⚠ same residue
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.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-arg185trp (accessed [today's date]).

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