Is CELSR1 p.Phe2518Leu (c.7554C>A) pathogenic?

CELSR1 p.Phe2518Leu (c.7554C>A) is classified Benign/Likely benign in CELSR1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-12-03). AlphaMissense: likely pathogenic (0.9402); Common (popmax 7.39%, afr) — too common for a highly-penetrant pathogenic allele; Associated with lymphatic malformation 9.

What condition is associated with CELSR1 p.Phe2518Leu (c.7554C>A)?

CELSR1 p.Phe2518Leu (c.7554C>A) is associated with lymphatic malformation 9 (ClinVar).

What do computational predictors say about CELSR1 p.Phe2518Leu (c.7554C>A)?

AlphaMissense predicts likely pathogenic (score 0.9402) — an in-silico prediction, not a clinical call.

CELSR1 p.Phe2518Leu

Q: How common is CELSR1 p.Phe2518Leu (c.7554C>A) in the general population?

CELSR1 p.Phe2518Leu (c.7554C>A) is common (popmax 7.39%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.7554C>A · rs116079347 · VCV786700

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9402 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.39%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

lymphatic malformation 9

Computational evidence

Protein change
AlphaMissense	0.9402	likely pathogenic
REVEL	0.303	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.17	GERP -2.2
Regional constraint	o/e 0.99	unconstrained · MANE · 46 kb · p 0.53 · regional, not allelic
Overall
CADD	18.27	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 7.39% African / African-American · 5,548/75,026 alleles

Filtering AF 7.23% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.17%

Overall 0.417% 6,728/1,613,368 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.39%	14
Remaining individualsnot grpmax-eligible	0.606%	165
Middle Eastern	0.446%	224
Admixed American	0.37%	270
European (non-Finnish)	0.045%	2,222
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,934
South Asian	0.0154%	6,504
Finnishnot grpmax-eligible	0.00158%	63,478

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.Phe2518Leu
Coding: c.7554C>A
MANE Select: NM_001378328
dbSNP: rs116079347
Type: single nucleotide variant
Location: chr22:46377091 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 2518: a UniProt-annotated variant site (in lmphm9)

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.Phe2518= Benign ★★ same residue
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

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-phe2518leu (accessed [today's date]).

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