Is CELSR3 p.Ala415Val (c.1244C>T) pathogenic?

CELSR3 p.Ala415Val (c.1244C>T) is classified Uncertain significance in CELSR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-15). AlphaMissense: ambiguous (0.4756); Very rare (popmax 0.00186%, nfe).

How common is CELSR3 p.Ala415Val (c.1244C>T) in the general population?

CELSR3 p.Ala415Val (c.1244C>T) is very rare (popmax 0.00186%, nfe) (gnomAD).

What do computational predictors say about CELSR3 p.Ala415Val (c.1244C>T)?

AlphaMissense predicts ambiguous (score 0.4756) — an in-silico prediction, not a clinical call.

CELSR3 p.Ala415Val

c.1244C>T · VCV4000257

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4756 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00186%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4756	ambiguous
REVEL	0.187	benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 1,031 bp · p 5.2e-11 · regional, not allelic
Overall
CADD	31.0	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 0.00186% European (non-Finnish) · 22/1,179,792 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00149% 24/1,612,482 alleles · very rare exomes 24/1,460,228 · genomes 0/152,254 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00186%	53,627
Remaining individualsnot grpmax-eligible	0.0016%	62,464
Finnishnot grpmax-eligible	0.00159%	62,738

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.Ala415Val
Coding: c.1244C>T
MANE Select: NM_001407
Type: single nucleotide variant
Location: chr3:48661391 (GRCh38)
Gene constraint: LOEUF 0.344 · pLI 1.00 (gnomAD)
Residue 415: the cadherin 1 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-ala415val (accessed [today's date]).

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