Is CELSR2 p.Arg2812Trp (c.8434C>T) pathogenic?

CELSR2 p.Arg2812Trp (c.8434C>T) is classified Likely benign in CELSR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-19). AlphaMissense: likely benign (0.0789); Rare (popmax 0.245%, nfe).

How common is CELSR2 p.Arg2812Trp (c.8434C>T) in the general population?

CELSR2 p.Arg2812Trp (c.8434C>T) is rare (popmax 0.245%, nfe) (gnomAD).

What do computational predictors say about CELSR2 p.Arg2812Trp (c.8434C>T)?

AlphaMissense predicts likely benign (score 0.0789) — an in-silico prediction, not a clinical call.

CELSR2 p.Arg2812Trp

c.8434C>T · rs149683589 · VCV1649663

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0789 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.245%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.0789	likely benign
REVEL	0.128	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 1.7	GERP -1.3, phastCons 0.9
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 2.9e-09 · regional, not allelic
Overall
CADD	15.44	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 0.245% European (non-Finnish) · 2,884/1,178,702 alleles

Filtering AF 0.237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.234%

Overall 0.194% 3,118/1,611,108 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.245%	409
Remaining individualsnot grpmax-eligible	0.168%	594
Admixed American	0.108%	930
Ashkenazi Jewishnot grpmax-eligible	0.0444%	2,254
African / African-American	0.0427%	2,342
Finnishnot grpmax-eligible	0.0251%	3,987
Middle Eastern	0.0165%	6,046
South Asian	0.00331%	30,239

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.Arg2812Trp
Coding: c.8434C>T
MANE Select: NM_001408
dbSNP: rs149683589
Type: single nucleotide variant
Location: chr1:109273261 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Residue 2812: a UniProt-annotated variant site (found in a patient with congenital hydrocephalus; uncertain significance); the 'disordered' region

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

Similar variants

CELSR2 p.Arg2812Gln Uncertain significance ★ ⚠ same residue
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

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-arg2812trp (accessed [today's date]).

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