Is CELSR3 p.Arg995Trp (c.2983C>T) pathogenic?

CELSR3 p.Arg995Trp (c.2983C>T) is classified Uncertain significance in CELSR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely benign (0.3224); Ultra-rare (popmax 0.0132%, sas).

How common is CELSR3 p.Arg995Trp (c.2983C>T) in the general population?

CELSR3 p.Arg995Trp (c.2983C>T) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

What do computational predictors say about CELSR3 p.Arg995Trp (c.2983C>T)?

AlphaMissense predicts likely benign (score 0.3224) — an in-silico prediction, not a clinical call.

CELSR3 p.Arg995Trp

c.2983C>T · rs531319649 · VCV2591937

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3224 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.3224	likely benign
REVEL	0.697	pathogenic-leaning
⇒ REVEL calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.12, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 12 kb · p 9.5e-43 · regional, not allelic
Overall
CADD	26.2	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 0.0132% South Asian · 12/91,092 alleles

Filtering AF 0.0075% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00242% 39/1,614,168 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,591
Admixed American	0.00666%	15,006
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
East Asian	0.00223%	44,890
European (non-Finnish)	0.00161%	62,107
Remaining individualsnot grpmax-eligible	0.0016%	62,510
African / African-American	0.00133%	75,036

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: CELSR3
Protein: p.Arg995Trp
Coding: c.2983C>T
MANE Select: NM_001407
dbSNP: rs531319649
Type: single nucleotide variant
Location: chr3:48659652 (GRCh38)
Gene constraint: LOEUF 0.344 · pLI 1.00 (gnomAD)
Residue 995: the cadherin 7 domain

Full CELSR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CELSR3 p.Arg995Gln Uncertain significance ★ same residue
CELSR3 p.Ala2862Val Uncertain significance ★★ ⚠ same type
CELSR3 p.Arg2345His Uncertain significance ★★ ⚠ same type
CELSR3 p.Gly2265Ser Uncertain significance ★★ ⚠ same type
CELSR3 p.Phe282Ser Uncertain significance ★★ ⚠ same type
CELSR3 p.Val1107Met Uncertain significance ★★ same type
CELSR3 p.Arg2886= Likely benign ★★ same type
CELSR3 p.Arg3189Gln Benign/Likely benign ★★ 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/celsr3-p-arg995trp (accessed [today's date]).

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