Is CLPSL2 p.Pro68Thr (c.202C>A) pathogenic?

CLPSL2 p.Pro68Thr (c.202C>A) is classified Uncertain significance in CLPSL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely pathogenic (0.9096); Absent from gnomAD v4.1.

How common is CLPSL2 p.Pro68Thr (c.202C>A) in the general population?

CLPSL2 p.Pro68Thr (c.202C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLPSL2 p.Pro68Thr (c.202C>A)?

AlphaMissense predicts likely pathogenic (score 0.9096) — an in-silico prediction, not a clinical call.

CLPSL2 p.Pro68Thr

c.202C>A · VCV4835416

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9096 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9096	likely pathogenic
REVEL	0.228	benign-leaning
SaProt	LLR -6.51	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 3.3	GERP 1.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,828 bp · p 0.7 · regional, not allelic
Overall
CADD	24.0	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

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: CLPSL2
Protein: p.Pro68Thr
Coding: c.202C>A
MANE Select: NM_207409
Type: single nucleotide variant
Location: chr6:35777576 (GRCh38)
Gene constraint: LOEUF 1.356 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 83.50
Residue 68: a disulfide bond

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-pro68thr (accessed [today's date]).

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