Is CELSR3 p.Thr654Met (c.1961C>T) pathogenic?

CELSR3 p.Thr654Met (c.1961C>T) is classified Benign/Likely benign in CELSR3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-30). AlphaMissense: likely benign (0.284); Rare (popmax 0.483%, eas).

How common is CELSR3 p.Thr654Met (c.1961C>T) in the general population?

CELSR3 p.Thr654Met (c.1961C>T) is rare (popmax 0.483%, eas) (gnomAD).

What do computational predictors say about CELSR3 p.Thr654Met (c.1961C>T)?

AlphaMissense predicts likely benign (score 0.284) — an in-silico prediction, not a clinical call.

CELSR3 p.Thr654Met

c.1961C>T · rs140688880 · VCV2653803

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.284 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.483%, eas)

Computational evidence

Protein change
AlphaMissense	0.284	likely benign
REVEL	0.46	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 1,031 bp · p 5.2e-11 · regional, not allelic
Overall
CADD	28.4	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 0.483% East Asian · 217/44,888 alleles

Filtering AF 0.431% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.41%

Overall 0.079% 1,275/1,614,110 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.582%	172
East Asiangrpmax	0.483%	207
South Asian	0.119%	843
Remaining individualsnot grpmax-eligible	0.0752%	1,330
Middle Eastern	0.0495%	2,021
European (non-Finnish)	0.0441%	2,269
Admixed American	0.00999%	10,006
African / African-American	0.00266%	37,536

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr654Met
Coding: c.1961C>T
MANE Select: NM_001407
dbSNP: rs140688880
Type: single nucleotide variant
Location: chr3:48660674 (GRCh38)
Gene constraint: LOEUF 0.344 · pLI 1.00 (gnomAD)
Residue 654: the cadherin 4 domain

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

Similar variants

CELSR3 p.Thr654= Likely benign ★ 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-thr654met (accessed [today's date]).

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