Is CLASP2 p.Ala1251Pro (c.3751G>C) pathogenic?

CLASP2 p.Ala1251Pro (c.3751G>C) is classified Uncertain significance in CLASP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely pathogenic (0.9168); Absent from gnomAD v4.1.

How common is CLASP2 p.Ala1251Pro (c.3751G>C) in the general population?

CLASP2 p.Ala1251Pro (c.3751G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLASP2 p.Ala1251Pro (c.3751G>C)?

AlphaMissense predicts likely pathogenic (score 0.9168) — an in-silico prediction, not a clinical call.

CLASP2 p.Ala1251Pro

c.3751G>C · VCV4229346

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9168 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9168	likely pathogenic
REVEL	0.306	indeterminate
SaProt	LLR -6.49	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 94 kb · p 3.9e-16 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A1039P vs ClinVar A1251P) — verify the residue.

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: CLASP2
Protein: p.Ala1251Pro
Coding: c.3751G>C
MANE Select: NM_001365631
Type: single nucleotide variant
Location: chr3:33535269 (GRCh38)
Gene constraint: LOEUF 0.365 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.98 · 7 PDB
Residue 1251: an α-helix; the 'interaction with rsn and localization to the golgi and kinetochores' region; the 'required for cortical localization' region

Full CLASP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLASP2 c.1949-9C>T Benign ★★ same type
CLASP2 p.Gly57= Benign ★★ same type
CLASP2 p.Ser544= Benign ★★ same type
CLASP2 c.2068+1G>A Uncertain significance ★ same type
CLASP2 c.2455-1137A>C Uncertain significance ★ same type
CLASP2 p.Ala1209Gly Uncertain significance ★ ⚠ same type
CLASP2 p.Ala1402Val Uncertain significance ★ ⚠ same type
CLASP2 p.Ala1496Pro 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/clasp2-p-ala1251pro (accessed [today's date]).

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