Is CELSR2 p.Phe2706Leu (c.8118C>G) pathogenic?

CELSR2 p.Phe2706Leu (c.8118C>G) is classified Uncertain significance in CELSR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). AlphaMissense: likely pathogenic (0.7326); Very rare (popmax 0.0022%, nfe).

How common is CELSR2 p.Phe2706Leu (c.8118C>G) in the general population?

CELSR2 p.Phe2706Leu (c.8118C>G) is very rare (popmax 0.0022%, nfe) (gnomAD).

What do computational predictors say about CELSR2 p.Phe2706Leu (c.8118C>G)?

AlphaMissense predicts likely pathogenic (score 0.7326) — an in-silico prediction, not a clinical call.

CELSR2 p.Phe2706Leu

c.8118C>G · VCV4000227

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7326 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.7326	likely pathogenic
REVEL	0.109	moderately benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.84	GERP 0.84, phastCons 0.75
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 2.9e-09 · regional, not allelic
Overall
CADD	20.2	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

Grpmax group 0.0022% European (non-Finnish) · 26/1,179,810 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00161% 26/1,613,264 alleles · very rare

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: CELSR2
Protein: p.Phe2706Leu
Coding: c.8118C>G
MANE Select: NM_001408
Type: single nucleotide variant
Location: chr1:109272703 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Residue 2706: the 'disordered' region

Full CELSR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CELSR2 c.8338+1G>C Uncertain significance ★★ same type
CELSR2 p.Ala1114Val Uncertain significance ★★ ⚠ same type
CELSR2 p.Ala2145Thr Uncertain significance ★★ ⚠ same type
CELSR2 p.Ala2574Thr Uncertain significance ★★ ⚠ same type
CELSR2 p.Arg1171Gln Uncertain significance ★★ ⚠ same type
CELSR2 p.Arg1328His Uncertain significance ★★ ⚠ same type
CELSR2 p.Arg1400His Uncertain significance ★★ same type
CELSR2 p.Arg1978Gln 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/celsr2-p-phe2706leu (accessed [today's date]).

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