Is CELSR1 p.Ala700Val (c.2099C>T) pathogenic?

CELSR1 p.Ala700Val (c.2099C>T) is classified Uncertain significance in CELSR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-05). AlphaMissense: likely benign (0.2356); Ultra-rare (popmax 0.0227%, afr).

How common is CELSR1 p.Ala700Val (c.2099C>T) in the general population?

CELSR1 p.Ala700Val (c.2099C>T) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about CELSR1 p.Ala700Val (c.2099C>T)?

AlphaMissense predicts likely benign (score 0.2356) — an in-silico prediction, not a clinical call.

CELSR1 p.Ala700Val

c.2099C>T · VCV3831327

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2356 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2356	likely benign
REVEL	0.36	indeterminate
SaProt	LLR -6.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 71 kb · p 0.73 · regional, not allelic
Overall
CADD	23.4	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

Grpmax group 0.0227% African / African-American · 17/74,896 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.0018% 29/1,612,006 alleles · ultra-rare exomes 16/1,459,884 · genomes 13/152,122 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,406
Admixed American	0.00667%	14,989
Remaining individualsnot grpmax-eligible	0.0048%	20,819
East Asian	0.00223%	44,870
South Asian	0.0011%	91,048
European (non-Finnish)	0.000254%	393,303

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: CELSR1
Protein: p.Ala700Val
Coding: c.2099C>T
MANE Select: NM_001378328
Type: single nucleotide variant
Location: chr22:46535072 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 700: a UniProt-annotated variant site (in lmphm9); the cadherin 5 domain

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

Similar variants

CELSR1 p.Ala2442Val Uncertain significance ★★ ⚠ same type
CELSR1 p.Ala2955Thr Uncertain significance ★★ ⚠ same type
CELSR1 p.Ala396Ser Uncertain significance ★★ ⚠ same type
CELSR1 p.Ala617Ser Uncertain significance ★★ ⚠ same type
CELSR1 p.Arg1323Gln Uncertain significance ★★ ⚠ same type
CELSR1 p.Arg1379His Uncertain significance ★★ ⚠ same type
CELSR1 p.Arg1643Gln Uncertain significance ★★ ⚠ same type
CELSR1 p.Arg1720Trp 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/celsr1-p-ala700val (accessed [today's date]).

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