Is CACYBP p.Pro187Ser (c.559C>T) pathogenic?

CACYBP p.Pro187Ser (c.559C>T) is classified Uncertain significance in CACYBP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely pathogenic (0.9771); Very rare (popmax 0.00305%, nfe).

How common is CACYBP p.Pro187Ser (c.559C>T) in the general population?

CACYBP p.Pro187Ser (c.559C>T) is very rare (popmax 0.00305%, nfe) (gnomAD).

What do computational predictors say about CACYBP p.Pro187Ser (c.559C>T)?

AlphaMissense predicts likely pathogenic (score 0.9771) — an in-silico prediction, not a clinical call.

CACYBP p.Pro187Ser

c.559C>T · VCV4218119

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9771 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00305%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9771	likely pathogenic
REVEL	0.394	indeterminate
SaProt	LLR -9.52	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.89, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 9,895 bp · p 1.4e-09 · regional, not allelic
Overall
CADD	22.7	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 0.00305% European (non-Finnish) · 36/1,179,006 alleles

Filtering AF 0.00224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00248% 40/1,612,348 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,197
European (non-Finnish)grpmax	0.00305%	32,750
African / African-American	0.00267%	37,403

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CACYBP
Protein: p.Pro187Ser
Coding: c.559C>T
MANE Select: NM_014412
Type: single nucleotide variant
Location: chr1:175009951 (GRCh38)
Gene constraint: LOEUF 1.441 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.05 · 3 PDB
Residue 187: the sgs domain; the 'interaction with skp1' region; the 'interaction with s100a6' region

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

Similar variants

CACYBP p.Thr109= Benign ★★ same type
CACYBP p.Arg208Gln Uncertain significance ★ ⚠ same type
CACYBP p.Arg26Gly Uncertain significance ★ ⚠ same type
CACYBP p.Gln7His Uncertain significance ★ ⚠ same type
CACYBP p.Glu184Gly Uncertain significance ★ ⚠ same type
CACYBP p.Glu227Gly Uncertain significance ★ ⚠ same type
CACYBP p.Ile152Thr Uncertain significance ★ ⚠ same type
CACYBP p.Leu120Pro 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/cacybp-p-pro187ser (accessed [today's date]).

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