Is CELSR1 p.Ala335Val (c.1004C>T) pathogenic?

CELSR1 p.Ala335Val (c.1004C>T) is classified Uncertain significance in CELSR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-27). AlphaMissense: ambiguous (0.514); Very rare (popmax 8.47e-05%, nfe); Associated with lymphatic malformation 9.

What condition is associated with CELSR1 p.Ala335Val (c.1004C>T)?

CELSR1 p.Ala335Val (c.1004C>T) is associated with lymphatic malformation 9 (ClinVar).

How common is CELSR1 p.Ala335Val (c.1004C>T) in the general population?

CELSR1 p.Ala335Val (c.1004C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CELSR1 p.Ala335Val (c.1004C>T)?

AlphaMissense predicts ambiguous (score 0.514) — an in-silico prediction, not a clinical call.

CELSR1 p.Ala335Val

c.1004C>T · VCV4883836

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.514 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

lymphatic malformation 9

Computational evidence

Protein change
AlphaMissense	0.514	ambiguous
REVEL	0.159	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 0.69, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,320 bp · p 0.15 · regional, not allelic
Overall
CADD	21.8	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 8.47e-05% European (non-Finnish) · 1/1,180,006 alleles

Overall 6.85e-05% 1/1,460,412 alleles · very rare

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.Ala335Val
Coding: c.1004C>T
MANE Select: NM_001378328
Type: single nucleotide variant
Location: chr22:46536167 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 335: a UniProt-annotated variant site (in lmphm9); the cadherin 1 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.Ala2955Thr Uncertain significance ★★ ⚠ same condition
CELSR1 p.Ala617Ser 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-ala335val (accessed [today's date]).

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