Is SLF2 p.Pro18Leu (c.53C>T) pathogenic?

SLF2 p.Pro18Leu (c.53C>T) is classified Uncertain significance in SLF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.5645); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with SLF2 p.Pro18Leu (c.53C>T)?

SLF2 p.Pro18Leu (c.53C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SLF2 p.Pro18Leu (c.53C>T) in the general population?

SLF2 p.Pro18Leu (c.53C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about SLF2 p.Pro18Leu (c.53C>T)?

AlphaMissense predicts likely pathogenic (score 0.5645) — an in-silico prediction, not a clinical call.

SLF2 p.Pro18Leu

c.53C>T · VCV4631540

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5645 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5645	likely pathogenic
REVEL	0.183	benign-leaning
SaProt	LLR -7.53	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 2.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 12 kb · p 0.68 · regional, not allelic
Overall
CADD	29.0	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 0.00167% Admixed American · 1/59,882 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,612,586 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,882
European (non-Finnish)	0.00017%	589,755

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: SLF2
Protein: p.Pro18Leu
Coding: c.53C>T
MANE Select: NM_018121
Type: single nucleotide variant
Location: chr10:100913163 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.80 · 1 PDB
Residue 18: the 'disordered' region

Full SLF2 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

Similar variants

SLF2 p.Gln756Arg Uncertain significance ★★ ⚠ same condition
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SLF2 c.3486+22T>G Uncertain significance ★ same condition
SLF2 p.Ala1145Thr Uncertain significance ★ ⚠ same condition
SLF2 p.Ala139Val Uncertain significance ★ ⚠ same condition
SLF2 p.Ala526Thr Uncertain significance ★ ⚠ same condition
SLF2 p.Ala644Val Uncertain significance ★ ⚠ same condition
SLF2 p.Arg1046Cys Uncertain significance ★ ⚠ 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/slf2-p-pro18leu (accessed [today's date]).

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