Is CELSR1 p.Arg2312Pro (c.6935G>C) pathogenic?

CELSR1 p.Arg2312Pro (c.6935G>C) is classified Benign in CELSR1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0778); Common (popmax 5.2%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CELSR1 p.Arg2312Pro (c.6935G>C)?

AlphaMissense predicts likely benign (score 0.0778) — an in-silico prediction, not a clinical call.

CELSR1 p.Arg2312Pro

Q: How common is CELSR1 p.Arg2312Pro (c.6935G>C) in the general population?

CELSR1 p.Arg2312Pro (c.6935G>C) is common (popmax 5.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6935G>C · rs7287089 · VCV782761

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0778 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.2%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0778	likely benign
REVEL	0.025	moderately 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 -8.9	GERP -2.6
Regional constraint	o/e 0.99	unconstrained · MANE · 46 kb · p 0.53 · regional, not allelic
Overall
CADD	0.219	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 5.2% African / African-American · 3,833/73,714 alleles

Filtering AF 5.06% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.01%

Overall 0.302% 4,715/1,563,818 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.2%	19
Ashkenazi Jewishnot grpmax-eligible	0.47%	213
Admixed American	0.453%	221
Remaining individualsnot grpmax-eligible	0.404%	247
Middle Eastern	0.267%	374
European (non-Finnish)	0.0199%	5,028
South Asian	0.0129%	7,741

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.Arg2312Pro
Coding: c.6935G>C
MANE Select: NM_001378328
dbSNP: rs7287089
Type: single nucleotide variant
Location: chr22:46381999 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 2312: a UniProt-annotated variant site (in lmphm9); a UniProt-annotated variant site (does not affect protein localization to the cell membrane); the gain-b domain; the 'disordered' region

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-arg2312pro (accessed [today's date]).

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