Is CIPC p.Pro75Leu (c.224C>T) pathogenic?

CIPC p.Pro75Leu (c.224C>T) is classified Uncertain significance in CIPC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely benign (0.0685); Ultra-rare (popmax 0.0411%, nfe).

How common is CIPC p.Pro75Leu (c.224C>T) in the general population?

CIPC p.Pro75Leu (c.224C>T) is ultra-rare (popmax 0.0411%, nfe) (gnomAD).

What do computational predictors say about CIPC p.Pro75Leu (c.224C>T)?

AlphaMissense predicts likely benign (score 0.0685) — an in-silico prediction, not a clinical call.

CIPC p.Pro75Leu

c.224C>T · VCV4229123

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0685 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0411%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0685	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -3.4
Regional constraint	o/e 0.86	unconstrained · MANE · 8,606 bp · p 0.0016 · regional, not allelic
Overall
CADD	9.999	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0411% European (non-Finnish) · 485/1,180,028 alleles

Filtering AF 0.0381% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0368%

Overall 0.031% 501/1,614,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0411%	2,433
Remaining individualsnot grpmax-eligible	0.016%	6,248
South Asian	0.00439%	22,770
East Asian	0.00223%	44,892
African / African-American	0.00134%	74,894

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: CIPC
Protein: p.Pro75Leu
Coding: c.224C>T
MANE Select: NM_033426
Type: single nucleotide variant
Location: chr14:77109899 (GRCh38)
Gene constraint: LOEUF 0.64 · pLI 0.44 (gnomAD)
Structure: AlphaFold pLDDT 58.88
Residue 75: the 'disordered' region

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

Similar variants

CIPC p.Ala220Thr Uncertain significance ★ ⚠ same type
CIPC p.Ala373Ser Uncertain significance ★ ⚠ same type
CIPC p.Arg29His Uncertain significance ★ ⚠ same type
CIPC p.Arg301Cys Uncertain significance ★ ⚠ same type
CIPC p.Arg301His Uncertain significance ★ ⚠ same type
CIPC p.Arg310Gln Uncertain significance ★ ⚠ same type
CIPC p.Arg310Trp Uncertain significance ★ ⚠ same type
CIPC p.Asn288His 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/cipc-p-pro75leu (accessed [today's date]).

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