Is FAT4 p.Glu4792Asp (c.14376A>C) pathogenic?

FAT4 p.Glu4792Asp (c.14376A>C) is classified Uncertain significance in FAT4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-20). AlphaMissense: ambiguous (0.5391); Ultra-rare (popmax 0.0283%, amr); Associated with van Maldergem syndrome 2.

What condition is associated with FAT4 p.Glu4792Asp (c.14376A>C)?

FAT4 p.Glu4792Asp (c.14376A>C) is associated with van Maldergem syndrome 2, Hennekam lymphangiectasia-lymphedema syndrome 2 (ClinVar).

How common is FAT4 p.Glu4792Asp (c.14376A>C) in the general population?

FAT4 p.Glu4792Asp (c.14376A>C) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

What do computational predictors say about FAT4 p.Glu4792Asp (c.14376A>C)?

AlphaMissense predicts ambiguous (score 0.5391) — an in-silico prediction, not a clinical call.

FAT4 p.Glu4792Asp

c.14376A>C · rs200724983 · VCV1490379

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5391 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Conditions

van Maldergem syndrome 2

Computational evidence

Protein change
AlphaMissense	0.5391	ambiguous
REVEL	0.495	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.42	GERP -3.5, phastCons 0.002
Regional constraint	o/e 0.98	unconstrained · MANE · 175 kb · p 0.071 · regional, not allelic
Overall
CADD	13.68	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM E4790D vs ClinVar E4792D) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0283% Admixed American · 17/60,010 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.0018% 29/1,614,088 alleles · ultra-rare exomes 25/1,461,844 · genomes 4/152,244 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0283%	3,530
Remaining individualsnot grpmax-eligible	0.0032%	31,253
European (non-Finnish)	0.000847%	118,003

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.Glu4792Asp
Coding: c.14376A>C
MANE Select: NM_001291303
dbSNP: rs200724983
Type: single nucleotide variant
Location: chr4:125491192 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 (gnomAD)

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-glu4792asp (accessed [today's date]).

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