Is CELSR2 p.Thr1680= (c.5040A>C) pathogenic?

CELSR2 p.Thr1680= (c.5040A>C) is classified Likely benign in CELSR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-14). Ultra-rare (popmax 0.0166%, nfe).

How common is CELSR2 p.Thr1680= (c.5040A>C) in the general population?

CELSR2 p.Thr1680= (c.5040A>C) is ultra-rare (popmax 0.0166%, nfe) (gnomAD).

CELSR2 p.Thr1680=

c.5040A>C · rs377023561 · VCV1563584

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.5	GERP -3.6
Overall
CADD	1.667	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% European (non-Finnish) · 194/1,168,674 alleles

Filtering AF 0.0147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0139%

Overall 0.0139% 222/1,598,766 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0365%	2,736
European (non-Finnish)grpmax	0.0166%	6,024
Remaining individualsnot grpmax-eligible	0.00486%	20,562
Admixed American	0.00335%	29,824

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: CELSR2
Protein: p.Thr1680=
Coding: c.5040A>C
MANE Select: NM_001408
dbSNP: rs377023561
Type: single nucleotide variant
Location: chr1:109264116 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Residue 1680: the laminin g-like 2 domain

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-thr1680 (accessed [today's date]).

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