Is CELSR2 p.Thr695Met (c.2084C>T) pathogenic?

CELSR2 p.Thr695Met (c.2084C>T) is classified Benign in CELSR2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-13). AlphaMissense: likely benign (0.0836); Low-frequency (popmax 1.33%, eas); Associated with CELSR2-related disorder.

What condition is associated with CELSR2 p.Thr695Met (c.2084C>T)?

CELSR2 p.Thr695Met (c.2084C>T) is associated with CELSR2-related disorder (ClinVar).

How common is CELSR2 p.Thr695Met (c.2084C>T) in the general population?

CELSR2 p.Thr695Met (c.2084C>T) is low-frequency (popmax 1.33%, eas) (gnomAD).

What do computational predictors say about CELSR2 p.Thr695Met (c.2084C>T)?

AlphaMissense predicts likely benign (score 0.0836) — an in-silico prediction, not a clinical call.

CELSR2 p.Thr695Met

c.2084C>T · rs117469174 · VCV3050522

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0836 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.33%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

CELSR2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0836	likely benign
REVEL	0.231	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 6	GERP 1, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 6,488 bp · p 1.6e-09 · regional, not allelic
Overall
CADD	25.9	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 1.33% East Asian · 596/44,882 alleles

Filtering AF 1.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.2%

Overall 0.0466% 752/1,613,988 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.33%	75
Ashkenazi Jewishnot grpmax-eligible	0.0912%	1,097
Remaining individualsnot grpmax-eligible	0.0576%	1,736
South Asian	0.034%	2,938
Middle Eastern	0.0165%	6,062
Admixed American	0.00666%	15,007
European (non-Finnish)	0.00475%	21,072
African / African-American	0.00133%	75,056

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.Thr695Met
Coding: c.2084C>T
MANE Select: NM_001408
dbSNP: rs117469174
Type: single nucleotide variant
Location: chr1:109252163 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Residue 695: the cadherin 5 domain

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

Disease context

CELSR2-related disorder

Similar variants

CELSR2 p.Thr695Ala Uncertain significance ★ ⚠ same residue
CELSR2 p.Thr695= Likely benign ★ same residue
CELSR2 p.Arg426Ter Uncertain significance same condition
CELSR2 p.Arg881Ter Uncertain significance same condition
CELSR2 p.Ala2579= Likely benign same condition
CELSR2 p.Arg2015= Benign same condition
CELSR2 p.Arg2191His Likely benign same condition
CELSR2 p.Asn1182= Likely benign same condition

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-thr695met (accessed [today's date]).

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