Is SPINK5 p.Ser7Pro (c.19T>C) pathogenic?

SPINK5 p.Ser7Pro (c.19T>C) is classified Uncertain significance in SPINK5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-02). AlphaMissense: likely benign (0.0725); Absent from gnomAD v4.1; Associated with ichthyosis linearis circumflexa.

What condition is associated with SPINK5 p.Ser7Pro (c.19T>C)?

SPINK5 p.Ser7Pro (c.19T>C) is associated with ichthyosis linearis circumflexa (ClinVar).

How common is SPINK5 p.Ser7Pro (c.19T>C) in the general population?

SPINK5 p.Ser7Pro (c.19T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SPINK5 p.Ser7Pro (c.19T>C)?

AlphaMissense predicts likely benign (score 0.0725) — an in-silico prediction, not a clinical call.

SPINK5 p.Ser7Pro

c.19T>C · rs1752512482 · VCV1010105

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0725 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ichthyosis linearis circumflexa

Computational evidence

Protein change
AlphaMissense	0.0725	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -8.15	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 0.064	GERP -1, phastCons 0.017
Regional constraint	o/e 0.92	unconstrained · MANE · 73 kb · p 0.0064 · regional, not allelic
Overall
CADD	2.895	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SPINK5
Protein: p.Ser7Pro
Coding: c.19T>C
MANE Select: NM_006846
dbSNP: rs1752512482
Type: single nucleotide variant
Location: chr5:148064063 (GRCh38)
Gene constraint: LOEUF 0.908 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.37 · 6 PDB

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

Disease context

ichthyosis linearis circumflexa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SPINK5 p.Ser7= Likely benign ★ 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-ser7pro (accessed [today's date]).

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