Is SPPL2B p.Pro535Ser (c.1603C>T) pathogenic?

SPPL2B p.Pro535Ser (c.1603C>T) is classified Uncertain significance in SPPL2B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-15). AlphaMissense: likely benign (0.0677); Absent from gnomAD v4.1.

How common is SPPL2B p.Pro535Ser (c.1603C>T) in the general population?

SPPL2B p.Pro535Ser (c.1603C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SPPL2B p.Pro535Ser (c.1603C>T)?

AlphaMissense predicts likely benign (score 0.0677) — an in-silico prediction, not a clinical call.

SPPL2B p.Pro535Ser

c.1603C>T · rs2512117002 · VCV2350601

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0677 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.0677	likely benign
SaProt	LLR -6.27	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.74	GERP -1.4
Regional constraint	o/e 1.02	unconstrained · MANE · 24 kb · p 0.58 · regional, not allelic
Overall
CADD	5.199	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; SaProt is an independent agreement signal.

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: SPPL2B
Protein: p.Pro535Ser
Coding: c.1603C>T
MANE Select: NM_152988
dbSNP: rs2512117002
Type: single nucleotide variant
Location: chr19:2353033 (GRCh38)
Gene constraint: LOEUF 1.108 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.62
Residue 535: the 'disordered' region

Full SPPL2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SPPL2B p.Ala268Thr Uncertain significance ★ ⚠ same type
SPPL2B p.Leu246Val Uncertain significance ★ ⚠ same type
SPPL2B p.Leu246His Likely benign ★ same type
SPPL2B p.Ser60Gly Likely benign ★ 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/sppl2b-p-pro535ser (accessed [today's date]).

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