Is CELSR2 p.Pro2020Ala (c.6058C>G) pathogenic?

CELSR2 p.Pro2020Ala (c.6058C>G) is classified Uncertain significance in CELSR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-23). AlphaMissense: likely benign (0.1776); Ultra-rare (popmax 0.05%, amr).

How common is CELSR2 p.Pro2020Ala (c.6058C>G) in the general population?

CELSR2 p.Pro2020Ala (c.6058C>G) is ultra-rare (popmax 0.05%, amr) (gnomAD).

What do computational predictors say about CELSR2 p.Pro2020Ala (c.6058C>G)?

AlphaMissense predicts likely benign (score 0.1776) — an in-silico prediction, not a clinical call.

CELSR2 p.Pro2020Ala

c.6058C>G · rs186529449 · VCV2204833

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1776 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.05%, amr)

Computational evidence

Protein change
AlphaMissense	0.1776	likely benign
REVEL	0.412	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 2.9e-09 · regional, not allelic
Overall
CADD	22.4	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 0.05% Admixed American · 30/60,028 alleles

Filtering AF 0.0359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0312%

Overall 0.0128% 206/1,614,160 alleles · ultra-rare exomes 170/1,461,874 · genomes 36/152,286 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.05%	2,001
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.016%	6,251
European (non-Finnish)	0.0129%	7,763
Finnishnot grpmax-eligible	0.00468%	21,346
East Asian	0.00446%	22,435
African / African-American	0.004%	25,014
South Asian	0.00329%	30,364

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.Pro2020Ala
Coding: c.6058C>G
MANE Select: NM_001408
dbSNP: rs186529449
Type: single nucleotide variant
Location: chr1:109267592 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)

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-pro2020ala (accessed [today's date]).

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