Is CELSR3 p.Arg1395Ser (c.4183C>A) pathogenic?

CELSR3 p.Arg1395Ser (c.4183C>A) is classified Uncertain significance in CELSR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: ambiguous (0.5091); Very rare (popmax 0.000933%, nfe).

How common is CELSR3 p.Arg1395Ser (c.4183C>A) in the general population?

CELSR3 p.Arg1395Ser (c.4183C>A) is very rare (popmax 0.000933%, nfe) (gnomAD).

What do computational predictors say about CELSR3 p.Arg1395Ser (c.4183C>A)?

AlphaMissense predicts ambiguous (score 0.5091) — an in-silico prediction, not a clinical call.

CELSR3 p.Arg1395Ser

c.4183C>A · VCV4225416

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5091 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000933%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5091	ambiguous
REVEL	0.358	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 12 kb · p 9.5e-43 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000933% European (non-Finnish) · 11/1,178,438 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000683% 11/1,610,728 alleles · very rare exomes 11/1,458,354 · genomes 0/152,374 · joint denominator

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: CELSR3
Protein: p.Arg1395Ser
Coding: c.4183C>A
MANE Select: NM_001407
Type: single nucleotide variant
Location: chr3:48656914 (GRCh38)
Gene constraint: LOEUF 0.344 · pLI 1.00 (gnomAD)
Residue 1395: the egf-like 1; calcium-binding domain

Full CELSR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CELSR3 p.Ala2862Val Uncertain significance ★★ ⚠ same type
CELSR3 p.Arg2345His Uncertain significance ★★ ⚠ same type
CELSR3 p.Gly2265Ser Uncertain significance ★★ ⚠ same type
CELSR3 p.Phe282Ser Uncertain significance ★★ ⚠ same type
CELSR3 p.Val1107Met Uncertain significance ★★ same type
CELSR3 p.Arg2886= Likely benign ★★ same type
CELSR3 p.Arg3189Gln Benign/Likely benign ★★ same type
CELSR3 p.Arg3201Gln Benign ★★ 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/celsr3-p-arg1395ser (accessed [today's date]).

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