Is SLIT3 p.Ser1345Pro (c.4033T>C) pathogenic?

SLIT3 p.Ser1345Pro (c.4033T>C) is classified Uncertain significance in SLIT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-03). AlphaMissense: likely benign (0.0741); Ultra-rare (popmax 0.0134%, eas).

How common is SLIT3 p.Ser1345Pro (c.4033T>C) in the general population?

SLIT3 p.Ser1345Pro (c.4033T>C) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about SLIT3 p.Ser1345Pro (c.4033T>C)?

AlphaMissense predicts likely benign (score 0.0741) — an in-silico prediction, not a clinical call.

SLIT3 p.Ser1345Pro

c.4033T>C · VCV3445632

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0741 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0741	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -5.90	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 0.36	GERP -4.2, phastCons 0.001
Overall
CADD	7.599	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

Grpmax group 0.0134% East Asian · 6/44,890 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.000372% 6/1,613,752 alleles · ultra-rare exomes 4/1,461,542 · genomes 2/152,210 · 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: SLIT3
Protein: p.Ser1345Pro
Coding: c.4033T>C
MANE Select: NM_003062
Type: single nucleotide variant
Location: chr5:168671292 (GRCh38)
Structure: AlphaFold pLDDT 80.28
Residue 1345: the egf-like 7 domain

Full SLIT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SLIT3 p.Arg682Gln Uncertain significance ★★ ⚠ same type
SLIT3 p.Gly1518Ser Uncertain significance ★★ ⚠ same type
SLIT3 p.Lys1348Asn Uncertain significance ★★ ⚠ same type
SLIT3 p.Met798Thr Uncertain significance ★★ ⚠ same type
SLIT3 p.Pro1122Gln Uncertain significance ★★ ⚠ same type
SLIT3 p.Thr535Asn Uncertain significance ★★ ⚠ same type
SLIT1 c.2970-7C>T Benign ★★ same type
SLIT1 p.Ala437= 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/slit3-p-ser1345pro (accessed [today's date]).

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