Is CLPSL2 p.Leu19Phe (c.55C>T) pathogenic?

CLPSL2 p.Leu19Phe (c.55C>T) is classified Uncertain significance in CLPSL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.0694); Ultra-rare (popmax 0.0471%, afr).

How common is CLPSL2 p.Leu19Phe (c.55C>T) in the general population?

CLPSL2 p.Leu19Phe (c.55C>T) is ultra-rare (popmax 0.0471%, afr) (gnomAD).

What do computational predictors say about CLPSL2 p.Leu19Phe (c.55C>T)?

AlphaMissense predicts likely benign (score 0.0694) — an in-silico prediction, not a clinical call.

CLPSL2 p.Leu19Phe

c.55C>T · rs934099089 · VCV2389018

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0694 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0471%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0694	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -8.21	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 0.081	GERP -2
Regional constraint	o/e 0.97	unconstrained · MANE · 2,828 bp · p 0.7 · regional, not allelic
Overall
CADD	0.668	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 0.0471% African / African-American · 32/67,928 alleles

Filtering AF 0.0343% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.00278% 41/1,472,860 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0471%	2,123
Admixed American	0.012%	8,354
Remaining individualsnot grpmax-eligible	0.00529%	18,919
European (non-Finnish)	8.93e-05%	1,119,820

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: CLPSL2
Protein: p.Leu19Phe
Coding: c.55C>T
MANE Select: NM_207409
dbSNP: rs934099089
Type: single nucleotide variant
Location: chr6:35776673 (GRCh38)
Gene constraint: LOEUF 1.356 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 83.50

Full CLPSL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLPSL2 p.Ala54Asp Uncertain significance ★ ⚠ same type
CLPSL2 p.Ala54Gly Uncertain significance ★ ⚠ same type
CLPSL2 p.Ala57Val Uncertain significance ★ ⚠ same type
CLPSL2 p.Arg81Trp Uncertain significance ★ ⚠ same type
CLPSL2 p.Arg95Cys Uncertain significance ★ ⚠ same type
CLPSL2 p.Arg96Trp Uncertain significance ★ ⚠ same type
CLPSL2 p.Asn75Ser Uncertain significance ★ ⚠ same type
CLPSL2 p.Gly10Ala Uncertain significance ★ ⚠ 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/clpsl2-p-leu19phe (accessed [today's date]).

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