Is CELSR1 p.Ile587Val (c.1759A>G) pathogenic?

CELSR1 p.Ile587Val (c.1759A>G) is classified Benign in CELSR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.1425); Common (popmax 5.65%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CELSR1 p.Ile587Val (c.1759A>G)?

AlphaMissense predicts likely benign (score 0.1425) — an in-silico prediction, not a clinical call.

CELSR1 p.Ile587Val

Q: How common is CELSR1 p.Ile587Val (c.1759A>G) in the general population?

CELSR1 p.Ile587Val (c.1759A>G) is common (popmax 5.65%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1759A>G · rs34141466 · VCV777760

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1425 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.65%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1425	likely benign
REVEL	0.184	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.041	GERP 0.09, phastCons 0.005
Regional constraint	o/e 0.99	unconstrained · MANE · 71 kb · p 0.73 · regional, not allelic
Overall
CADD	18.01	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 5.65% African / African-American · 4,236/75,022 alleles

Filtering AF 5.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.45%

Overall 0.31% 4,991/1,609,114 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.65%	18
Remaining individualsnot grpmax-eligible	0.454%	220
Admixed American	0.406%	246
Middle Eastern	0.265%	378
South Asian	0.0199%	5,024
European (non-Finnish)	0.0165%	6,072
East Asian	0.00223%	44,846

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.Ile587Val
Coding: c.1759A>G
MANE Select: NM_001378328
dbSNP: rs34141466
Type: single nucleotide variant
Location: chr22:46535412 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 587: a UniProt-annotated variant site (in lmphm9); a UniProt-annotated variant site (in); the cadherin 4 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-ile587val (accessed [today's date]).

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