Is SKI p.Pro15Leu (c.44C>T) pathogenic?

SKI p.Pro15Leu (c.44C>T) is classified Uncertain significance in SKI (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-22). AlphaMissense: ambiguous (0.3762); Very rare (popmax 9.56e-05%, nfe).

How common is SKI p.Pro15Leu (c.44C>T) in the general population?

SKI p.Pro15Leu (c.44C>T) is very rare (popmax 9.56e-05%, nfe) (gnomAD).

What do computational predictors say about SKI p.Pro15Leu (c.44C>T)?

AlphaMissense predicts ambiguous (score 0.3762) — an in-silico prediction, not a clinical call.

SKI p.Pro15Leu

c.44C>T · rs2527575277 · VCV2429712

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3762 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.56e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3762	ambiguous
REVEL	0.585	indeterminate
SaProt	LLR -5.76	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.8	GERP 1.1, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 253 bp · p 0.099 · regional, not allelic
Overall
CADD	26.4	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 9.56e-05% European (non-Finnish) · 1/1,046,200 alleles

Overall 7.35e-05% 1/1,360,892 alleles · very rare exomes 1/1,211,866 · genomes 0/149,026 · 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: SKI
Protein: p.Pro15Leu
Coding: c.44C>T
MANE Select: NM_003036
dbSNP: rs2527575277
Type: single nucleotide variant
Location: chr1:2228810 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB

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

Similar variants

SKI p.Pro15= Likely benign ★ same residue
SKI p.Gly116Glu Pathogenic/Likely pathogenic ★★ same type
SKI p.Gly117Arg Pathogenic/Likely pathogenic ★★ same type
SKI p.Gly117Ser Pathogenic/Likely pathogenic ★★ same type
SKI p.Gly34Cys Pathogenic ★★ ⚠ same type
SKI p.Gly34Ser Pathogenic/Likely pathogenic ★★ ⚠ same type
SKI p.Gly34Val Pathogenic ★★ ⚠ same type
SKI p.Leu32Val Pathogenic ★★ ⚠ 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/ski-p-pro15leu (accessed [today's date]).

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