Is CELSR1 p.Leu1995Pro (c.5984T>C) pathogenic?

CELSR1 p.Leu1995Pro (c.5984T>C) is classified Benign in CELSR1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-08-02). AlphaMissense: likely benign (0.0377); Common (popmax 66.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with CELSR1-related disorder.

What condition is associated with CELSR1 p.Leu1995Pro (c.5984T>C)?

CELSR1 p.Leu1995Pro (c.5984T>C) is associated with CELSR1-related disorder (ClinVar).

What do computational predictors say about CELSR1 p.Leu1995Pro (c.5984T>C)?

AlphaMissense predicts likely benign (score 0.0377) — an in-silico prediction, not a clinical call.

CELSR1 p.Leu1995Pro

Q: How common is CELSR1 p.Leu1995Pro (c.5984T>C) in the general population?

CELSR1 p.Leu1995Pro (c.5984T>C) is common (popmax 66.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.5984T>C · rs6008794 · VCV3057210

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0377 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 66.9%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

CELSR1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0377	likely benign
REVEL	0.077	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.96	GERP -0.68, phastCons 0.1
Regional constraint	o/e 0.99	unconstrained · MANE · 46 kb · p 0.53 · regional, not allelic
Overall
CADD	13.76	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 66.9% African / African-American · 49,964/74,676 alleles

Filtering AF 66.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 66.2%

Overall 17.9% 287,458/1,609,796 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	66.9%	1
Amishnot grpmax-eligible	19.1%	5
Ashkenazi Jewishnot grpmax-eligible	17.9%	6
Remaining individualsnot grpmax-eligible	17.8%	6
European (non-Finnish)	16.4%	6
Middle Eastern	16.3%	6
South Asian	13.2%	8
Admixed American	11.9%	8
Finnishnot grpmax-eligible	11.2%	9
East Asian	0.941%	106

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.Leu1995Pro
Coding: c.5984T>C
MANE Select: NM_001378328
dbSNP: rs6008794
Type: single nucleotide variant
Location: chr22:46391797 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 1995: a UniProt-annotated variant site (in lmphm9); a UniProt-annotated variant site (in); the egf-like 8; calcium-binding domain; a disulfide bond

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

Disease context

CELSR1-related disorder

Similar variants

CELSR1 p.Arg1643Gln Uncertain significance ★★ ⚠ same condition
CELSR1 p.Pro46His Uncertain significance ★★ ⚠ same condition
CELSR1 p.Ser2825Leu Uncertain significance ★★ same condition
CELSR1 p.Val2338Ile Uncertain significance ★★ ⚠ same condition
CELSR1 p.Leu979Phe Likely pathogenic ★ ⚠ same condition
CELSR1 p.Ala2486Pro Uncertain significance ★ same condition
CELSR1 p.Asp1201Asn Conflicting classifications of pathogenicity ★ same condition
CELSR1 p.Cys1934= Uncertain significance ★ same condition

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-leu1995pro (accessed [today's date]).

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