Is CNN1 p.Ser2Phe (c.5C>T) pathogenic?

CNN1 p.Ser2Phe (c.5C>T) is classified Uncertain significance in CNN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-06). AlphaMissense: ambiguous (0.3841); Ultra-rare (popmax 0.0169%, mid).

How common is CNN1 p.Ser2Phe (c.5C>T) in the general population?

CNN1 p.Ser2Phe (c.5C>T) is ultra-rare (popmax 0.0169%, mid) (gnomAD).

What do computational predictors say about CNN1 p.Ser2Phe (c.5C>T)?

AlphaMissense predicts ambiguous (score 0.3841) — an in-silico prediction, not a clinical call.

CNN1 p.Ser2Phe

c.5C>T · VCV4004291

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3841 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3841	ambiguous
REVEL	0.094	moderately benign-leaning
SaProt	LLR -10.70	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP -0.76, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 11 kb · p 1.5e-05 · regional, not allelic
Overall
CADD	26.2	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 0.0169% Middle Eastern · 1/5,926 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000314% 5/1,591,388 alleles · ultra-rare exomes 5/1,439,020 · genomes 0/152,368 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0169%	5,926
European (non-Finnish)	0.000343%	291,857

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.Ser2Phe
Coding: c.5C>T
MANE Select: NM_001299
Type: single nucleotide variant
Location: chr19:11538932 (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-ser2phe (accessed [today's date]).

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