Is SPINK5 p.Pro45Ser (c.133C>T) pathogenic?

SPINK5 p.Pro45Ser (c.133C>T) is classified Conflicting classifications of pathogenicity in SPINK5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-07-25). AlphaMissense: likely benign (0.1086); Very rare (popmax 0.00339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SPINK5 p.Pro45Ser (c.133C>T)?

SPINK5 p.Pro45Ser (c.133C>T) is associated with Inborn genetic diseases, ichthyosis linearis circumflexa (ClinVar).

How common is SPINK5 p.Pro45Ser (c.133C>T) in the general population?

SPINK5 p.Pro45Ser (c.133C>T) is very rare (popmax 0.00339%, nfe) (gnomAD).

What do computational predictors say about SPINK5 p.Pro45Ser (c.133C>T)?

AlphaMissense predicts likely benign (score 0.1086) — an in-silico prediction, not a clinical call.

SPINK5 p.Pro45Ser

c.133C>T · rs1025545434 · VCV2188755

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1086 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1086	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -9.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.42	GERP -3.9
Regional constraint	o/e 0.92	unconstrained · MANE · 73 kb · p 0.0064 · regional, not allelic
Overall
CADD	0.645	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 0.00339% European (non-Finnish) · 40/1,179,294 alleles

Filtering AF 0.00256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00254% 41/1,612,728 alleles · very rare exomes 41/1,460,650 · genomes 0/152,078 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00339%	29,482
Remaining individualsnot grpmax-eligible	0.0016%	62,418

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: SPINK5
Protein: p.Pro45Ser
Coding: c.133C>T
MANE Select: NM_006846
dbSNP: rs1025545434
Type: single nucleotide variant
Location: chr5:148070374 (GRCh38)
Gene constraint: LOEUF 0.908 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.37 · 6 PDB
Residue 45: the kazal-like 1; atypical domain

Full SPINK5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ichthyosis linearis circumflexa

Similar variants

SPINK5 p.Pro45His Uncertain significance ★ ⚠ same residue
SPINK5 c.1302+4A>T Pathogenic ★★ same condition
SPINK5 c.1430+1G>T Pathogenic/Likely pathogenic ★★ same condition
SPINK5 c.1431-12G>A Pathogenic/Likely pathogenic ★★ same condition
SPINK5 c.2240+1G>A Pathogenic ★★ same condition
SPINK5 c.2740-1G>C Likely pathogenic ★★ same condition
SPINK5 c.666+1G>A Pathogenic/Likely pathogenic ★★ same condition
SPINK5 c.81+2T>A Pathogenic ★★ same condition

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/spink5-p-pro45ser (accessed [today's date]).

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