Is CELSR1 p.Ala617Ser (c.1849G>T) pathogenic?

CELSR1 p.Ala617Ser (c.1849G>T) is classified Uncertain significance in CELSR1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-27). AlphaMissense: likely benign (0.0718); Ultra-rare (popmax 0.0493%, mid); Associated with lymphatic malformation 9.

What condition is associated with CELSR1 p.Ala617Ser (c.1849G>T)?

CELSR1 p.Ala617Ser (c.1849G>T) is associated with lymphatic malformation 9 (ClinVar).

How common is CELSR1 p.Ala617Ser (c.1849G>T) in the general population?

CELSR1 p.Ala617Ser (c.1849G>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about CELSR1 p.Ala617Ser (c.1849G>T)?

AlphaMissense predicts likely benign (score 0.0718) — an in-silico prediction, not a clinical call.

CELSR1 p.Ala617Ser

c.1849G>T · rs201866541 · VCV2208761

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0718 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

lymphatic malformation 9

Computational evidence

Protein change
AlphaMissense	0.0718	likely benign
REVEL	0.03	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 -0.84	GERP -1.1
Regional constraint	o/e 0.99	unconstrained · MANE · 71 kb · p 0.73 · regional, not allelic
Overall
CADD	0.547	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00715%

Overall 0.00236% 38/1,611,802 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
Remaining individualsnot grpmax-eligible	0.0048%	20,813
European (non-Finnish)	0.00271%	36,874

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: CELSR1
Protein: p.Ala617Ser
Coding: c.1849G>T
MANE Select: NM_001378328
dbSNP: rs201866541
Type: single nucleotide variant
Location: chr22:46535322 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 617: a UniProt-annotated variant site (in lmphm9); the cadherin 4 domain

Full CELSR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lymphatic malformation 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CELSR1 p.Ala617Thr Uncertain significance ★ ⚠ same residue
CELSR1 p.Ala2955Thr Uncertain significance ★★ ⚠ same condition
CELSR1 p.Arg1323Gln Uncertain significance ★★ ⚠ same condition
CELSR1 p.Arg1643Gln Uncertain significance ★★ ⚠ same condition
CELSR1 p.Arg2795Lys Uncertain significance ★★ ⚠ same condition
CELSR1 p.Arg973Pro Uncertain significance ★★ same condition
CELSR1 p.Asp2004Asn Uncertain significance ★★ same condition
CELSR1 p.Asp3007Ala Uncertain significance ★★ ⚠ 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/celsr1-p-ala617ser (accessed [today's date]).

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