Is CELSR1 p.Ala2486Pro (c.7456G>C) pathogenic?

CELSR1 p.Ala2486Pro (c.7456G>C) is classified Uncertain significance in CELSR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-03). AlphaMissense: ambiguous (0.5041); Absent from gnomAD v4.1; Associated with Mild NDD.

What condition is associated with CELSR1 p.Ala2486Pro (c.7456G>C)?

CELSR1 p.Ala2486Pro (c.7456G>C) is associated with Mild NDD (ClinVar).

How common is CELSR1 p.Ala2486Pro (c.7456G>C) in the general population?

CELSR1 p.Ala2486Pro (c.7456G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CELSR1 p.Ala2486Pro (c.7456G>C)?

AlphaMissense predicts ambiguous (score 0.5041) — an in-silico prediction, not a clinical call.

CELSR1 p.Ala2486Pro

c.7456G>C · VCV4073566

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5041 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Mild NDD

Computational evidence

Protein change
AlphaMissense	0.5041	ambiguous
REVEL	0.307	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.067	GERP -2.3
Regional constraint	o/e 0.99	unconstrained · MANE · 46 kb · p 0.53 · regional, not allelic
Overall
CADD	22.5	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: CELSR1
Protein: p.Ala2486Pro
Coding: c.7456G>C
MANE Select: NM_001378328
Type: single nucleotide variant
Location: chr22:46377189 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 2486: a UniProt-annotated variant site (in lmphm9)

Full CELSR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Mild NDD

Similar variants

CELSR1 p.Arg1643Gln Uncertain significance ★★ ⚠ same condition
CELSR1 p.Pro46His Uncertain significance ★★ ⚠ same condition
CELSR1 p.Ser2825Leu Uncertain significance ★★ same condition
CELSR1 p.Val2338Ile Uncertain significance ★★ ⚠ same condition
CELSR1 p.Leu979Phe Likely pathogenic ★ ⚠ same condition
CELSR1 p.Asp1201Asn Conflicting classifications of pathogenicity ★ same condition
CELSR1 p.Cys1934= Uncertain significance ★ same condition
CELSR1 p.Gly68Ser 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/celsr1-p-ala2486pro (accessed [today's date]).

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