Is FAT4 p.Leu808Met (c.2422C>A) pathogenic?

FAT4 p.Leu808Met (c.2422C>A) is classified Uncertain significance in FAT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-03). AlphaMissense: likely benign (0.0901); Absent from gnomAD v4.1; Associated with Hennekam lymphangiectasia-lymphedema syndrome 2.

What condition is associated with FAT4 p.Leu808Met (c.2422C>A)?

FAT4 p.Leu808Met (c.2422C>A) is associated with Hennekam lymphangiectasia-lymphedema syndrome 2, van Maldergem syndrome 2 (ClinVar).

How common is FAT4 p.Leu808Met (c.2422C>A) in the general population?

FAT4 p.Leu808Met (c.2422C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FAT4 p.Leu808Met (c.2422C>A)?

AlphaMissense predicts likely benign (score 0.0901) — an in-silico prediction, not a clinical call.

FAT4 p.Leu808Met

c.2422C>A · VCV3589907

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0901 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Hennekam lymphangiectasia-lymphedema syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0901	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.56	GERP -0.41, phastCons 0.085
Regional constraint	o/e 0.98	unconstrained · MANE · 175 kb · p 0.071 · regional, not allelic
Overall
CADD	14.4	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FAT4
Protein: p.Leu808Met
Coding: c.2422C>A
MANE Select: NM_001291303
Type: single nucleotide variant
Location: chr4:125318833 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 (gnomAD)
Residue 808: the cadherin 8 domain

Full FAT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hennekam lymphangiectasia-lymphedema syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: van Maldergem syndrome 2

Similar variants

FAT4 p.Leu808= Likely benign ★ same residue
FAT4 p.Arg1902Ter Pathogenic/Likely pathogenic ★★ same condition
FAT4 p.Gln4530Ter Pathogenic/Likely pathogenic ★★ same condition
FAT4 c.5307+6T>A Uncertain significance ★★ same condition
FAT4 c.6843+4A>G Uncertain significance ★★ same condition
FAT4 p.Ala132Asp Uncertain significance ★★ ⚠ same condition
FAT4 p.Ala1984Thr Uncertain significance ★★ ⚠ same condition
FAT4 p.Ala198Val 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/fat4-p-leu808met (accessed [today's date]).

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