Is SPINK5 p.Pro656Ser (c.1966C>T) pathogenic?

SPINK5 p.Pro656Ser (c.1966C>T) is classified Uncertain significance in SPINK5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-05). AlphaMissense: likely benign (0.2862); Absent from gnomAD v4.1; Associated with ichthyosis linearis circumflexa.

What condition is associated with SPINK5 p.Pro656Ser (c.1966C>T)?

SPINK5 p.Pro656Ser (c.1966C>T) is associated with ichthyosis linearis circumflexa (ClinVar).

How common is SPINK5 p.Pro656Ser (c.1966C>T) in the general population?

SPINK5 p.Pro656Ser (c.1966C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SPINK5 p.Pro656Ser (c.1966C>T)?

AlphaMissense predicts likely benign (score 0.2862) — an in-silico prediction, not a clinical call.

SPINK5 p.Pro656Ser

c.1966C>T · rs2531771531 · VCV2134160

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2862 · 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	0.2862	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -7.64	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 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 73 kb · p 0.0064 · regional, not allelic
Overall
CADD	26.2	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.Pro656Ser
Coding: c.1966C>T
MANE Select: NM_006846
dbSNP: rs2531771531
Type: single nucleotide variant
Location: chr5:148114440 (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 656: the kazal-like 10 domain

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 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
SPINK5 c.81+5G>A Pathogenic/Likely 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-pro656ser (accessed [today's date]).

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