Is FAT4 p.Val1908Leu (c.5722G>T) pathogenic?

FAT4 p.Val1908Leu (c.5722G>T) is classified Uncertain significance in FAT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-03). AlphaMissense: likely benign (0.0717); Very rare (popmax 0.00017%, nfe); Associated with Hennekam lymphangiectasia-lymphedema syndrome 2.

What condition is associated with FAT4 p.Val1908Leu (c.5722G>T)?

FAT4 p.Val1908Leu (c.5722G>T) is associated with Hennekam lymphangiectasia-lymphedema syndrome 2, van Maldergem syndrome 2 (ClinVar).

How common is FAT4 p.Val1908Leu (c.5722G>T) in the general population?

FAT4 p.Val1908Leu (c.5722G>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about FAT4 p.Val1908Leu (c.5722G>T)?

AlphaMissense predicts likely benign (score 0.0717) — an in-silico prediction, not a clinical call.

FAT4 p.Val1908Leu

c.5722G>T · VCV3589972

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0717 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Hennekam lymphangiectasia-lymphedema syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0717	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.77	GERP -3.5, phastCons 0.099
Regional constraint	o/e 0.98	unconstrained · MANE · 175 kb · p 0.071 · regional, not allelic
Overall
CADD	7.952	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

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,346 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,612,764 alleles · very rare exomes 2/1,460,824 · genomes 1/151,940 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,420
European (non-Finnish)grpmax	0.00017%	589,671

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: FAT4
Protein: p.Val1908Leu
Coding: c.5722G>T
MANE Select: NM_001291303
Type: single nucleotide variant
Location: chr4:125408596 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 (gnomAD)
Residue 1908: the cadherin 18 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.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
FAT4 p.Ala2210= 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-val1908leu (accessed [today's date]).

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