Is CILP2 p.Pro174Leu (c.521C>T) pathogenic?

CILP2 p.Pro174Leu (c.521C>T) is classified Uncertain significance in CILP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-07). AlphaMissense: likely benign (0.0751); Ultra-rare (popmax 0.0816%, eas).

How common is CILP2 p.Pro174Leu (c.521C>T) in the general population?

CILP2 p.Pro174Leu (c.521C>T) is ultra-rare (popmax 0.0816%, eas) (gnomAD).

What do computational predictors say about CILP2 p.Pro174Leu (c.521C>T)?

AlphaMissense predicts likely benign (score 0.0751) — an in-silico prediction, not a clinical call.

CILP2 p.Pro174Leu

c.521C>T · rs202214502 · VCV3145065

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0751 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0816%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0751	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -4.75	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 2.4	GERP -0.26, phastCons 0.034
Regional constraint	o/e 1.04	unconstrained · MANE · 7,663 bp · p 0.074 · regional, not allelic
Overall
CADD	17.05	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 0.0816% East Asian · 27/33,098 alleles

Filtering AF 0.0576% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0495%

Overall 0.00703% 89/1,265,502 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.128%	783
East Asiangrpmax	0.0816%	1,226
African / African-American	0.00153%	65,484
European (non-Finnish)	9.96e-05%	1,004,352

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: CILP2
Protein: p.Pro174Leu
Coding: c.521C>T
MANE Select: NM_153221
dbSNP: rs202214502
Type: single nucleotide variant
Location: chr19:19541175 (GRCh38)
Gene constraint: LOEUF 1.329 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.47
Residue 174: a disulfide bond; the tsp type-1 domain

Full CILP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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CILP2 p.Ala1045Val Uncertain significance ★ ⚠ same type
CILP2 p.Ala1076Val Uncertain significance ★ ⚠ same type
CILP2 p.Ala1096Val Uncertain significance ★ ⚠ same type
CILP2 p.Ala1109Val Uncertain significance ★ ⚠ same type
CILP2 p.Ala188Glu Uncertain significance ★ ⚠ same type
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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/cilp2-p-pro174leu (accessed [today's date]).

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