Is CYBC1 p.Ser23Phe (c.68C>T) pathogenic?

CYBC1 p.Ser23Phe (c.68C>T) is classified Uncertain significance in CYBC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-28). AlphaMissense: likely pathogenic (0.9718); Very rare (popmax 0.000344%, nfe).

How common is CYBC1 p.Ser23Phe (c.68C>T) in the general population?

CYBC1 p.Ser23Phe (c.68C>T) is very rare (popmax 0.000344%, nfe) (gnomAD).

What do computational predictors say about CYBC1 p.Ser23Phe (c.68C>T)?

AlphaMissense predicts likely pathogenic (score 0.9718) — an in-silico prediction, not a clinical call.

CYBC1 p.Ser23Phe

c.68C>T · rs1228932482 · VCV2100112

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9718 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000344%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9718	likely pathogenic · top 4% in CYBC1
REVEL	0.62	indeterminate
SaProt	LLR -12.36	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 5,247 bp · p 0.74 · regional, not allelic
Overall
CADD	32.0	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 0.000344% European (non-Finnish) · 4/1,163,760 alleles

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

Overall 0.000253% 4/1,580,418 alleles · very rare exomes 4/1,428,068 · genomes 0/152,350 · joint denominator

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: CYBC1
Protein: p.Ser23Phe
Coding: c.68C>T
MANE Select: NM_001033046
dbSNP: rs1228932482
Type: single nucleotide variant
Location: chr17:82449187 (GRCh38)
Gene constraint: LOEUF 1.556 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.65 · 1 PDB
Residue 23: a UniProt-annotated variant site (in cgd5; loss of protein expression; decreased pma-induced oxidative burst in neutrophils)

Full CYBC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYBC1 p.Arg129Trp Uncertain significance ★★ same type
CYBC1 p.Arg147Cys Uncertain significance ★★ ⚠ same type
CYBC1 p.Asp43Asn Uncertain significance ★★ ⚠ same type
CYBC1 p.Asp98Asn Uncertain significance ★★ ⚠ same type
CYBC1 p.Thr82Met Uncertain significance ★★ ⚠ same type
CYBC1 c.127+13C>A Benign/Likely benign ★★ same type
CYBC1 c.127+16C>T Likely benign ★★ same type
CYBC1 c.128-150G>T Benign ★★ 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/cybc1-p-ser23phe (accessed [today's date]).

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