Is CLSPN p.Ala543Pro (c.1627G>C) pathogenic?

CLSPN p.Ala543Pro (c.1627G>C) is classified Uncertain significance in CLSPN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-06). AlphaMissense: likely benign (0.129); Absent from gnomAD v4.1.

How common is CLSPN p.Ala543Pro (c.1627G>C) in the general population?

CLSPN p.Ala543Pro (c.1627G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLSPN p.Ala543Pro (c.1627G>C)?

AlphaMissense predicts likely benign (score 0.129) — an in-silico prediction, not a clinical call.

CLSPN p.Ala543Pro

c.1627G>C · VCV3834166

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.129 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.129	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -5.62	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 1.1	GERP -0.077, phastCons 0.17
Regional constraint	o/e 0.92	unconstrained · MANE · 27 kb · p 0.005 · regional, not allelic
Overall
CADD	21.4	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

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: CLSPN
Protein: p.Ala543Pro
Coding: c.1627G>C
MANE Select: NM_022111
Type: single nucleotide variant
Location: chr1:35753889 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 51.32 · 5 PDB

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

Similar variants

CLSPN p.Lys338= Benign ★★ same type
CLSPN p.Ala1222Asp Uncertain significance ★ ⚠ same type
CLSPN p.Ala126Val Uncertain significance ★ ⚠ same type
CLSPN p.Ala1295Val Uncertain significance ★ ⚠ same type
CLSPN p.Ala379Val Uncertain significance ★ ⚠ same type
CLSPN p.Ala450Thr Uncertain significance ★ ⚠ same type
CLSPN p.Ala578Thr Uncertain significance ★ ⚠ same type
CLSPN p.Ala816Val 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/clspn-p-ala543pro (accessed [today's date]).

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