Is FAT4 p.Arg1065= (c.3195A>G) pathogenic?

FAT4 p.Arg1065= (c.3195A>G) is classified Uncertain significance in FAT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). Very rare (popmax 0.00534%, afr); Associated with Hennekam lymphangiectasia-lymphedema syndrome 2.

What condition is associated with FAT4 p.Arg1065= (c.3195A>G)?

FAT4 p.Arg1065= (c.3195A>G) is associated with Hennekam lymphangiectasia-lymphedema syndrome 2, van Maldergem syndrome 2 (ClinVar).

How common is FAT4 p.Arg1065= (c.3195A>G) in the general population?

FAT4 p.Arg1065= (c.3195A>G) is very rare (popmax 0.00534%, afr) (gnomAD).

FAT4 p.Arg1065=

c.3195A>G · VCV3589926

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

Hennekam lymphangiectasia-lymphedema syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.31	donor gain · deltas
Pangolin	Δ0.66	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.38	GERP 0.82, phastCons 0.66
Overall
CADD	14.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,906 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,613,830 alleles · very rare

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.Arg1065=
Coding: c.3195A>G
MANE Select: NM_001291303
Type: single nucleotide variant
Location: chr4:125319606 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 (gnomAD)
Residue 1065: the cadherin 10 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-arg1065 (accessed [today's date]).

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