Is FAT4 p.Val2864= (c.8592G>A) pathogenic?

FAT4 p.Val2864= (c.8592G>A) is classified Benign/Likely benign in FAT4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-02). Common (popmax 5.03%, afr) — too common for a highly-penetrant pathogenic allele; Associated with van Maldergem syndrome 2.

What condition is associated with FAT4 p.Val2864= (c.8592G>A)?

FAT4 p.Val2864= (c.8592G>A) is associated with van Maldergem syndrome 2, Hennekam lymphangiectasia-lymphedema syndrome 2 (ClinVar).

FAT4 p.Val2864=

Q: How common is FAT4 p.Val2864= (c.8592G>A) in the general population?

FAT4 p.Val2864= (c.8592G>A) is common (popmax 5.03%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.8592G>A · rs111758803 · VCV384298

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 5.03%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

van Maldergem syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.49, phastCons 1
Overall
CADD	5.873	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.03% African / African-American · 3,771/75,008 alleles

Filtering AF 4.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.84%

Overall 0.261% 4,205/1,613,772 alleles · common exomes 1,996/1,461,578 · genomes 2,209/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.03%	20
Remaining individualsnot grpmax-eligible	0.328%	305
Admixed American	0.278%	359
Middle Eastern	0.149%	673
South Asian	0.00879%	11,380
European (non-Finnish)	0.00381%	26,219

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.Val2864=
Coding: c.8592G>A
MANE Select: NM_001291303
dbSNP: rs111758803
Type: single nucleotide variant
Location: chr4:125449602 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 (gnomAD)
Residue 2864: the cadherin 27 domain

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

Disease context

van Maldergem syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Hennekam lymphangiectasia-lymphedema 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-val2864 (accessed [today's date]).

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